Fused Ring Azadecalin Glucocorticoid Receptor Modulators

ABSTRACT

The present invention provides a novel class of fused ring azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/591,884, filed May 7, 2007, which is the U.S. National Stage entryunder §371 of PCT/US2005/008049, filed Mar. 9, 2005, which claims thebenefit of U.S. Provisional Patent Application No. 60/551,836, filedMar. 9, 2004, the contents of which are incorporated herein by referencein their entirety for all purposes.

BACKGROUND OF THE INVENTION

In most species, including man, the physiological glucocorticoid iscortisol (hydrocortisone). Glucocorticoids are secreted in response toACTH (corticotropin), which shows both circadian rhythm variation andelevations in response to stress and food. Cortisol levels areresponsive within minutes to many physical and psychological stresses,including trauma, surgery, exercise, anxiety and depression. Cortisol isa steroid and acts by binding to an intracellular, glucocorticoidreceptor (GR). In man, glucocorticoid receptors are present in twoforms: a ligand-binding GR-alpha of 777 amino acids; and, a GR-betaisoform which differs in only the last fifteen amino acids. The twotypes of GR have high affinity for their specific ligands, and areconsidered to function through the same transduction pathways.

The biologic effects of cortisol, including those caused byhypercortisolemia, can be modulated at the GR level using receptormodulators, such as agonists, partial agonists and antagonists. Severaldifferent classes of agents are able to block the physiologic effects ofGR-agonist binding. These antagonists include compositions which, bybinding to GR, block the ability of an agonist to effectively bind toand/or activate the GR. One such known GR antagonist, mifepristone, hasbeen found to be an effective anti-glucocorticoid agent in humans(Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone bindsto the GR with high affinity, with a dissociation constant (K_(d)) of10⁻⁹ M (Cadepond (1997) Annu. Rev. Med. 48:129).

Patients with some forms of psychiatric illnesses have been found tohave increased levels of cortisol (Krishnan (1992) Prog.Neuro-Psychopharmacol. & Biol. Psychiat. 16:913-920). For example, somedepressed individuals can be responsive to treatments which block theeffect of cortisol, as by administering GR antagonists (Van Look (1995)Human Reproduction Update 1:19-34). In one study, a patient withdepression secondary to Cushing's Syndrome (hyperadrenocorticism) wasresponsive to a high dose, up to 1400 mg per day, of GR antagonistmifepristone (Nieman (1985) J. Clin Endocrinol. Metab. 61:536). Anotherstudy which used mifepristone to treat Cushing's syndrome found that itimproved the patients' conditions, including their psychiatric status(Chrousos, pp 273-284, In: Baulieu, ed. The Antiprogestin Steroid RU 486and Human Fertility Control. Plenum Press, New York (1989), Sartor(1996) Clin. Obstetrics and Gynecol. 39:506-510).

Psychosis has also been associated with Cushing's syndrome (Gerson(1985) Can. J. Psychiatry 30:223-224; Saad (1984) Am. J. Med.76:759-766). Mifepristone has been used to treat acute psychiatricdisturbances secondary to Cushing's syndrome. One study showed that arelatively high dose of mifepristone (400 to 800 mg per day) was usefulin rapidly reversing acute psychosis in patients with severe CushingSyndrome due to adrenal cancers and ectopic secretion of ACTH from lungcancer (Van der Lely (1991) Ann. Intern. Med. 114:143; Van der Lely(1993) Pharmacy World & Science 15:89-90; Sartor (1996) supra).

A treatment for psychosis or the psychotic component of illnesses, suchas psychotic major depression, has recently been discovered (Schatzberget al., U.S. Pat. No. 6,150,349). The treatment includes administrationof an amount of a glucocorticoid receptor antagonist effective toameliorate the psychosis. The psychosis may also be associated withpsychotic major depression, Alzheimer's Disease and cocaine addiction.

Thus, there exists a great need for a more effective and safer treatmentfor illnesses and conditions associated with the glucocorticoidreceptors, including psychotic major depression. The present inventionfulfills these and other needs.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a compound having theformula:

In Formula (I), L¹ and L² are independently selected from a bond, —O—,—S—, S(O)—, —S(O₂)—, —C(O)—, —C(O)O—, —C(O)NH—, substituted orunsubstituted alkylene, and substituted or unsubstituted heteroalkylene.

The dashed line b is optionally a bond.

The ring A is selected from substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl.

R¹ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,—OR^(1A), C(O)NR^(1C)R^(1D), C(O)OR^(1A). R^(1A) is selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. R^(1C)and R^(1D) are selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.Alternatively R^(1C) and R^(1D) may be joined together with the nitrogenatom to which they are attached to form a substituted or unsubstitutedring optionally containing a second heteroatom selected from O, N or S.

R² is selected from substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl,—S(O₂)R^(2A), —S(O₂)NR^(2B)R^(2C), ═NOR^(2D). R^(2A), R^(2B), R^(2C),and R^(2D) are independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In another aspect, the present invention provides methods of treating adisorder or condition through modulating a glucocorticoid receptor. Themethod includes administering to a subject in need of such treatment, aneffective amount of the compound of the present invention.

In another aspect, the present invention provides methods of treating adisorder or condition through antagonizing a glucocorticoid receptor.The method includes administering to a subject in need of suchtreatment, an effective amount of the compound of the present invention.

In another aspect, the present invention provides methods of modulatinga glucocorticoid receptor including the steps of contacting aglucocorticoid receptor with an effective amount of the compound of thepresent invention and detecting a change in the activity of theglucocorticoid receptor.

In another aspect, the present invention provides a pharmaceuticalcomposition including a pharmaceutically acceptable excipient and thecompound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e. unbranched) or branched chain,or cyclic hydrocarbon radical, or combination thereof, which may befully saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated (i.e.C₁-C₁₀ means one to ten carbons). Examples of saturated hydrocarbonradicals include, but are not limited to, groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. Alkyl groups which arelimited to hydrocarbon groups are termed “homoalkyl”.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having five or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom selected fromthe group consisting of O, N, P, Si and S, and wherein the nitrogen andsulfur atoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) O, N, P and S and Si may beplaced at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH—CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, O—CH₃, —O—CH₂—CH₃, and —CN. Up to twoheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Similarly, the term “heteroalkylene” by itself or aspart of another substituent means a divalent radical derived fromheteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini (e.g., alkyleneoxy,alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Stillfurther, for alkylene and heteroalkylene linking groups, no orientationof the linking group is implied by the direction in which the formula ofthe linking group is written. For example, the formula —C(O)₂R′—represents both —C(O)₂R′— and —R′C(O)₂—. As described above, heteroalkylgroups, as used herein, include those groups that are attached to theremainder of the molecule through a heteroatom, such as —C(O)R′,—C(O)NR′, —NR′R″, —OR′, —SR′, and/or —S(O₂)R′. Where “heteroalkyl” isrecited, followed by recitations of specific heteroalkyl groups, such as—NR′R″ or the like, it will be understood that the terms heteroalkyl and—NR′R″ are not redundant or mutually exclusive. Rather, the specificheteroalkyl groups are recited to add clarity. Thus, the term“heteroalkyl” should not be interpreted herein as excluding specificheteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent which can be a single ring or multiplerings (preferably from 1 to 3 rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a carbon or heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl,1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl,4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below.

For brevity, the term “aryl” when used in combination with other tell is(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like). Likewise,the term “heteroarylalkyl” is meant to include those radicals in which aheteroaryl group is attached to an alkyl group.

The term “oxo” as used herein means an oxygen that is double bonded to acarbon atom.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Examples of substituents for each typeof radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR′″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR(SO₂)R, —CN and—NO₂ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″, R′″ and R″″ eachpreferably independently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g.,aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl,alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: halogen, —OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR(SO₂)R′, —CN and—NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C_(j)—C₄)alkoxy, andfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number ofopen valences on the aromatic ring system; and where R′, R″, R′″ and R″″are preferably independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. When a compound of the invention includes morethan one R group, for example, each of the R groups is independentlyselected as are each R′, R″, R′″ and R″″ groups when more than one ofthese groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′— or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″ and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

As used herein, the term “heteroatom” or “ring heteroatom” is meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., “Pharmaceutical Salts”, Journal ofPharmaceutical Science, 1977, 66, 1-19). Certain specific compounds ofthe present invention contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts.

Where two substituents are “optionally joined together to form a ring,”the two substituents are covalently bonded together with the atom oratoms to which the two substituents are joined to form a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted cycloalkyl, or a substituted orunsubstituted heterocycloalkyl ring.

The term “cortisol” refers to a family of compositions also referred toas hydrocortisone, and any synthetic or natural analogues thereof.

The term “glucocorticoid receptor” (“GR”) refers to a family ofintracellular receptors also referred to as the cortisol receptor, whichspecifically bind to cortisol and/or cortisol analogs (e.g.dexamethasone). The term includes isoforms of GR, recombinant GR andmutated GR.

The term “glucocorticoid receptor antagonist” refers to any compositionor compound which partially or completely inhibits (antagonizes) thebinding of a glucocorticoid receptor (GR) agonist, such as cortisol, orcortisol analogs, synthetic or natural, to a GR. A “specificglucocorticoid receptor antagonist” refers to any composition orcompound which inhibits any biological response associated with thebinding of a GR to an agonist. By “specific,” we intend the drug topreferentially bind to the GR rather than another nuclear receptors,such as mineralocorticoid receptor (MR) or progesterone receptor (PR).

“Fused ring azadecalin,” as used herein, means a glucocorticoid receptormodulator as described by any of the Formulae (I)-(XI) below. A fusedring azadecalin compound may also be referred to herein as a “copound ofthe present invention.”

The term “treating” refers to any indicia of success in the treatment oramelioration of an injury, pathology or condition, including anyobjective or subjective parameter such as abatement; remission;diminishing of symptoms or making the injury, pathology or conditionmore tolerable to the patient; slowing in the rate of degeneration ordecline; making the final point of degeneration less debilitating;improving a patient's physical or mental well-being. The treatment oramelioration of symptoms can be based on objective or subjectiveparameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,the methods of the invention successfully treat a patient's delirium bydecreasing the incidence of disturbances in consciousness or cognition.

An “additional ring heteroatom” refers to a heteroatom that foils partof a substituted or unsubstituted ring (e.g., a heterocycloalkyl orheteroaryl) that is not the point of attachment of the ring toward theazadecalin core. The azadecalin core is the fused ring portion of thecompound of Formula (I), excluding ring A.

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) —OH, —NH₂, —SH, —CN, —CF₃, —COOH, —C(O)NH₂, oxo, halogen,        unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted        cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,        unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —COOH, —C(O)NH₂,            halogen, unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            and heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —COOH, —C(O)NH₂,                halogen, unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, or heteroaryl, substituted with at least one                substituent selected from oxo, —OH, —NH₂, —SH, —CN,                —CF₃, halogen, unsubstituted alkyl, unsubstituted                heteroalkyl, unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, and unsubstituted                heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein means a “substituent group” as defined above, wherein eachsubstituted or unsubstituted alkyl is a substituted or unsubstitutedC₁-C₂₀ alkyl, each substituted or unsubstituted heteroalkyl is asubstituted or unsubstituted 2 to 20 membered heteroalkyl, eachsubstituted or unsubstituted cycloalkyl is a substituted orunsubstituted C₄-C₈ cycloalkyl, and each substituted or unsubstitutedheterocycloalkyl is a substituted or unsubstituted 4 to 8 memberedheterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein meansa “substituent group” as defined above, wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₈ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 8 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₅-C₇cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 5 to 7 membered heterocycloalkyl.

The compounds of the present invention may exist as salts. The presentinvention includes such salts. Examples of applicable salt forms includehydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates (eg (+)-tartrates,(−)-tartrates or mixtures thereof including racemic mixtures,succinates, benzoates and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in art.Also included are base addition salts such as sodium, potassium,calcium, ammonium, organic amino, or magnesium salt, or a similar salt.When compounds of the present invention contain relatively basicfunctionalities, acid addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples of acceptableacid addition salts include those derived from inorganic acids likehydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived organic acids like acetic, propionic,isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric,lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like. Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the enantiomers, racemates,diastereomers, tautomers, geometric isomers, stereoisometric forms thatmay be defined, in terms of absolute stereochemistry, as (R)-or (S)- or,as (D)- or (L)- for amino acids, and individual isomers are encompassedwithin the scope of the present invention. The compounds of the presentinvention do not include those which are known in art to be too unstableto synthesize and/or isolate. The present invention is meant to includecompounds in racemic and optically pure forms. Optically active (R)- and(S)-, or (D)- and (L)-isomers may be prepared using chiral synthons orchiral reagents, or resolved using conventional techniques.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

The terms “a,” “an,” or “a(n)”, when used in reference to a group ofsubstituents or “substituent group” herein, mean at least one. Forexample, where a compound is substituted with “an” alkyl or aryl, thecompound is optionally substituted with at least one alkyl and/or atleast one aryl, wherein each alkyl and/or aryl is optionally different.In another example, where a compound is substituted with “a”substitutent group, the compound is substituted with at least onesubstituent group, wherein each substitutent group is optionallydifferent.

Description of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, or physiological conditions.

The terms “treating” or “treatment” in reference to a particular diseaseincludes prevention of the disease.

DESCRIPTION OF THE EMBODIMENTS I. Glucocorticoid Receptor Modulators

It has now been discovered that fused ring azadecalin compounds arepotent modulators of glucocorticoid receptors (“GR”). GR modulatorstypically act as agonists, partial agonists or antagonists of GR therebyaffecting a wide array of cellular functions, physiological functionsand disease states.

Cortisol acts by binding to an intracellular glucocorticoid receptor. Inhumans, glucocorticoid receptors are present in two forms: aligand-binding GR-alpha of 777 amino acids; and, a GR-beta isoform thatdiffers in only the last fifteen amino acids. The two types of GR havehigh affinity for their specific ligands, and are considered to functionthrough the same transduction pathways.

GR modulators are typically efficacious agents for influencing importantcellular and physiological functions such as carbohydrate, protein andlipid metabolism; electrolyte and water balance; and functions of thecardiovascular system, kidney, central nervous system, immune system,skeletal muscle system and other organ and tissue systems. GR modulatorsmay also affect a wide variety of disease states, such as obesity,diabetes, cardiovascular disease, hypertension, Syndrome X, depression,anxiety, glaucoma, human immunodeficiency virus (HIV) or acquiredimmunodeficiency syndrome (AIDS), neurodegeneration (e.g. Alzheimer'sdisease and Parkinson's disease), cognition enhancement, Cushing'sSyndrome, Addison's Disease, osteoporosis, frailty, inflammatorydiseases (e.g., osteoarthritis, rheumatoid arthritis, asthma andrhinitis), adrenal function-related ailments, viral infection,immunodeficiency, immunomodulation, autoimmune diseases, allergies,wound healing, compulsive behavior, multi-drug resistance, addiction,psychosis, anorexia, cachexia, post-traumatic stress syndrome,post-surgical bone fracture, medical catabolism, and muscle frailty.

In a first aspect, the present invention provides a compound having theformula:

In Formula (I), L¹ and L² are independently selected from a bond, —O—,—S—, S(O)—, —S(O₂)—, —C(O)—, —C(O)O—, —C(O)NH—, substituted orunsubstituted alkylene, and substituted or unsubstituted heteroalkylene.

The dashed line b is optionally a bond.

The ring A is selected from substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

R¹ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,—OR^(1A), —NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), —C(O)OR^(1A). R^(1A) isselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. R^(1C)and R^(1D) are selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.Alternatively, R^(1C) and R^(1D) may be joined together with thenitrogen atom to which they are attached to form a substituted orunsubstituted ring optionally containing a second heteroatom selectedfrom O, N or S. In some embodiments, the substituted or unsubstitutedring is a 4 to 8 membered ring and the second heteroatom is a nitrogen.In other embodiments, where R¹ is a substituted or unsubstituted alkyl,the alkyl moiety is a substituted or unsubstituted C₁-C₂₀ alkyl (e.g. aC₆-C₂₀ alkyl).

R² is selected from substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl,—S(O₂)R^(2A), —S(O₂)NR^(2B)R^(2C), —NOR^(2D). R^(2A), R^(2B), R^(2C), orR^(2D) are independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

L¹ and L² may also be independently selected from a bond, substituted orunsubstituted (C₁-C₆)alkylene, and substituted or unsubstituted 2 to 5membered heteroalkylene. In a related embodiment, L¹ and L² areindependently selected from a bond and —C(O)—. In another relatedembodiment, L¹ and L² are independently selected from a bond andunsubstituted (C₁-C₆) alkylene.

In some embodiments, the ring A is selected from substituted orunsubstituted 5 to 6 membered heterocycloalkyl, and substituted orunsubstituted heteroaryl. A may also be selected from unsubstituted 5 to6 membered heterocycloalkyl including at least one heteroatom selectedfrom N, O and S; substituted 5 to 6 membered heterocycloalkyl having 1to 3 substituents and at least one ring heteroatom selected from N, Oand S; unsubstituted aryl having at least one heteroatom selected fromN, O and S; and substituted aryl having 1 to 3 substituents and at leastone ring heteroatom selected from N, O and S.

A variety of heterocycloalkyl groups are useful as A ring groups,including substituted or unsubstituted pyrrolidinyl, substituted orunsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl,substituted or unsubstituted imidazolyl, substituted or unsubstitutedfuranyl, substituted or unsubstituted oxazolyl, substituted orunsubstituted isoxazolyl, substituted or unsubstituted thienyl,substituted or unsubstituted thiazolyl, substituted or unsubstitutedisothiazolyl, substituted or unsubstituted pyridinyl, substituted orunsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, andsubstituted or unsubstituted pyrimidinyl and substituted orunsubstituted piperidinyl. In some embodiments, A is a substituted orunsubstituted pyrazolyl.

Where A is substituted, the substituent may be selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —NR^(3A)R^(3B), and —OR^(3C).The ring A substituent may also be selected from hydrogen, substitutedor unsubstituted (C₁-C₁₀) alkyl, substituted or unsubstituted 2-10membered heteroalkyl, substituted or unsubstituted (C₃-C₇) cycloalkyl,substituted or unsubstituted 3-7 membered heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl,—NR^(3A)R^(3B), and —OR^(3C). The ring A substituent may also beselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted aryl,—NR^(3A)R^(3B), and —OR^(3C). R^(3A) and R^(3B) are independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstitutedheterocycloalkyl, and substituted or unsubstituted heteroaryl. R^(3A)and R^(3B) are optionally joined to form a substituted or unsubstitutedring with the nitrogen to which they are attached, wherein the ringoptionally comprises an additional ring heteroatom. R^(3C) is a selectedfrom substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

R^(3A), R^(3B), and R^(3C) may be selected from substituted orunsubstituted (C₁-C₁₀) alkyl, substituted or unsubstituted 2-10 memberedheteroalkyl, substituted or unsubstituted (C₃-C₇) cycloalkyl,substituted or unsubstituted 3-7 membered heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In a related embodiment, A is substituted with at least twosubstituents. The first substituent is selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aryl, —NR^(3A)R^(3B), and—OR^(3C). The second substituent is selected from hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

R¹ may be selected from substituted or unsubstituted (C₁-C₁₀) alkyl,substituted or unsubstituted 2-10 membered heteroalkyl, substituted orunsubstituted (C₃-C₇) cycloalkyl, substituted or unsubstituted 3-7membered heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. In some embodiments, R¹ is asubstituted or unsubstituted (C₆-C₁₀) alkyl.

In some embodiments, R¹ has the formula:

In Formula (III), q is an integer selected from 1 to 5. In someembodiments, q is an integer selected from 1 to 3. The integer q mayalso be 1.

The symbol R^(1B) in Formula (III) may be selected from hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl,—NR^(1B1)R^(1B2), —OR^(1B3), —C(O)NR^(1B4)R^(1B5), and —S(O₂)R^(1B6). Inanother embodiment, R^(1B) is selected from hydrogen, substituted alkyl,substituted or unsubstituted heteroalkyl, substituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted aryl, andsubstituted or unsubstituted heteroaryl. In some embodiments, R^(1B) isselected from substituted or unsubstituted (C₁-C₁₀) alkyl, substitutedor unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted(C₃-C₇) cycloalkyl, substituted or unsubstituted 3-7 memberedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

R^(1B1) and R^(1B2) are independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —COR^(1B10), and —S(O₂)R^(1B9).R^(1B9) and R^(1B10) are independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. R^(1B1) and R^(1B2) areoptionally joined to form a substituted or unsubstituted ring with thenitrogen to which they are attached. The ring formed by R^(1B1) andR^(1B2) optionally includes an additional ring heteroatom. R^(1B1) andR^(1B2) may also be independently selected from substituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedheterocycloalkyl, and substituted or unsubstituted heteroaryl.

R^(1B3) is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. Insome embodiments, R^(1B3) is selected from hydrogen, substituted orunsubstituted heteroalkyl having a nitrogen; substituted orunsubstituted heterocycloalkyl having a ring nitrogen; substituted orunsubstituted heteroaryl having a ring nitrogen; and alkyl substitutedwith a substituted or unsubstituted heteroalkyl having a nitrogen,substituted or unsubstituted heterocycloalkyl having a ring nitrogen,and substituted or unsubstituted heteroaryl having a ring nitrogen.

R^(1B6) is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, and—NR^(1B7)R^(1B8). R^(1B7) and R^(1B8) are independently selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. R^(1B7)and R^(1B8) are optionally joined with the nitrogen to which they areattached to form a substituted or unsubstituted ring.

In a related embodiment, R^(1B) is selected from —C(O)NR^(1B4)R^(1B5)and substituted or unsubstituted heteroaryl having a ring nitrogen.R^(1B4) and R^(1B5) are independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. In some embodiments, R^(1B4)and R^(1B5) are independently selected from hydrogen; substituted orunsubstituted heteroalkyl having a nitrogen; substituted orunsubstituted heterocycloalkyl having a ring nitrogen; substituted orunsubstituted heteroaryl having a ring nitrogen; and alkyl substitutedwith a substituted or unsubstituted heteroalkyl having a nitrogen,substituted or unsubstituted heterocycloalkyl having a ring nitrogen,and substituted or unsubstituted heteroaryl having a ring nitrogen.R^(1B4) and R^(1B5) are optionally joined to form a substituted orunsubstituted ring with the nitrogen to which they are attached. Thering formed by R^(1B4) and R^(1B5) optionally contains an additionalheteroatom.

In another embodiment, R^(1B1), R^(1B2), R^(1B3), R^(1B4), R^(1B5),R^(1B6), R^(1B7), R^(1B8), R^(1B9) and R^(1B10) are independentlyselected from R^(1B) is selected from substituted or unsubstituted(C₁-C₁₀) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl,substituted or unsubstituted (C₃-C₇) cycloalkyl, substituted orunsubstituted 3-7 membered heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In someembodiments, the rings formed by R^(1B4) and R^(1B5), R^(1B7) andR^(1B8), and R^(1B1) and R^(1B) are independently selected from,substituted or unsubstituted 3-7 membered heterocycloalkyl andsubstituted or unsubstituted heteroaryl.

R^(1B1), R^(1B2), R^(1B3), R^(1B4) and R^(1B5) may also be independentlyselected from hydrogen and a substituted or unsubstituted ring, whereinthe ring optionally contains a nitrogen atom and at least one additionalring heteroatom.

R¹ may also have the formula:

In Formula (IV), R^(1B) is selected from hydrogen, —NR^(1B1)R^(1B2),—OR^(1B3), substituted or unsubstituted (C₁-C₁₀) alkyl, substituted orunsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted(C₃-C₇)cycloalkyl, substituted or unsubstituted 3-7 memberedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In an exemplary embodiment, R^(1A) is selected from hydrogen,substituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted2 to 10 membered heteroalkyl, substituted or unsubstituted C₃-C₇membered cycloalkyl, substituted or unsubstituted 3-7 memberedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl. R^(1C) and R^(1D) are independently selectedfrom hydrogen, substituted or unsubstituted C₁-C₁₀ alkyl, substituted orunsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstitutedC₃-C₇ membered cycloalkyl, substituted or unsubstituted 3-7 memberedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl. R^(1C) and R^(1D) may be joined together withthe nitrogen atom to which they are attached to form a substituted orunsubstituted heteroaryl of 4 to 8 membered heterocycloalkyl. In someembodiments, R^(1A) is hydrogen.

In some embodiments, R¹ is selected from OR^(1A), —NR^(1C)R^(1D),—C(O)R^(1A), and —C(O)NR^(1C)R^(1D). In a related embodiment, L¹ is asubstituted or unsubstituted (C₁-C₆)alkylene. In a further relatedembodiment, L¹ is an unsubstituted (C₁-C₆)alkylene.

In other embodiments, R¹ is selected from —C(O)OR^(1A),—C(O)NR^(1B)R^(1C), and L¹ is selected from a bond or substituted orunsubstituted (C₁-C₆)alkylene. In a related embodiment, L¹ is selectedfrom a bond or unsubstituted (C₁-C₆)alkylene

In still other embodiments, R¹ has the formula of formula (III) above,and L¹ is —C(O)—.

In an exemplary embodiment, R² is selected from substituted orunsubstituted (C₁-C₁₀) alkyl, substituted or unsubstituted 2-10 memberedheteroalkyl, substituted or unsubstituted (C₃-C₇) cycloalkyl,substituted or unsubstituted 3-7 membered heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In another exemplary embodiment, R^(2A), R^(2B), R^(2C), and R^(2D) areindependently selected from substituted or unsubstituted (C₁-C₁₀) alkyl,substituted or unsubstituted 2-10 membered heteroalkyl, substituted orunsubstituted (C₃-C₇) cycloalkyl, substituted or unsubstituted 3-7membered heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

R² may also have the formula:

In Formula (V), R^(2G) is selected from halogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl. In a related embodiment, R^(2G) is selectedfrom hydrogen, substituted or unsubstituted (C₁-C₁₀) alkyl, substitutedor unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted(C₃-C₇) cycloalkyl, substituted or unsubstituted 3-7 memberedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl. In another related embodiment, R^(2G) is abranched or unbranched (C₁-C₁₀) alkyl. The symbol t is an integerselected from 0 to 5.

One of skill in the art will immediately recognize that the value for tis limited by the number of ring members in ring J. For example, thesymbol t is an integer from 0 to 5 where J is a 6 or 7 memberedsubstituted or unsubstituted ring. The symbol t is an integer from 0 to4 where J is a 5 membered substituted or unsubstituted ring. The symbolt is an integer from 0 to 3 where J is a 4 membered substituted orunsubstituted ring. The symbol t is an integer from 0 to 2 where J is a3 membered substituted or unsubstituted ring.

In some embodiments, the symbol t is 1.

J is selected from substituted or unsubstituted ring selected fromsubstituted or unsubstituted (C₃-C₇) cycloalkyl, substituted orunsubstituted 3-7 membered heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In someembodiments, J is a substituted or unsubstituted ring selected fromsubstituted or unsubstituted 3-7 membered heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.

X is selected from a bond, —S(O₂)—, and —S(O₂)NR^(2I)—. R^(2I) isselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In someembodiments, R^(2I) is selected from substituted or unsubstituted(C₁-C₁₀) alkyl, substituted or unsubstituted 2-10 membered heteroalkyl,substituted or unsubstituted (C₃-C₇) cycloalkyl, substituted orunsubstituted 3-7 membered heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. Inanother embodiment, R^(2I) is selected from hydrogen, substituted orunsubstituted alkyl, and substituted or unsubstituted heteroalkyl.

In another exemplary embodiment, the compound of the present inventionhas the formula

In Formula (II), the dashed ring represents unsaturated, partiallysaturated, or fully saturated bonds within ring E. Thus, a double bondis optionally present at any of the bonds within ring E. The dashed lineb is optionally a bond.

Z¹ is selected from —NR⁵—, ═N—, —O—, and —S—. R⁵ is selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted aryl. R³ mayalso be selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted aryl. Alternatively, R⁵ may be selected from hydrogen andsubstituted or unsubstituted aryl. In another embodiment, R⁵ is ansubstituted or unsubstituted C₁-C₁₀ alkyl, or substituted orunsubstituted aryl. In some embodiments, R⁵ is an unsubstituted C₁-C₁₀alkyl, unsubstituted aryl, or fluoro-substituted aryl.

Z² is selected from —CR^(6A)R^(6B), —CR^(6A)—, —C(O)—, —NR^(6C)—, ═N—,—O—, —S—, —CR^(6A)R^(6B)—NR^(6C)—, ═CR^(6A)—NR^(6C)—, —CR^(6A)═N—,—CR^(6A)R^(6B)—N═, and ═CR^(6A)—N═. R^(6C) is selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl,and substituted or unsubstituted aryl. R^(6C) may also be selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aryl.

R^(6A) and R^(6B) are independently selected from hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted aryl, —NR^(6A1)R^(6A2), and —OR^(6A3). R^(6A) andR^(6C) are optionally joined together to form a substituted orunsubstituted ring, wherein the ring optionally comprises an additionalring heteroatom. R^(6A) and R^(6B) may also be independently selectedfrom hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aryl,—NR^(6A1)R^(6A2), and —OR^(6A3).

R^(6A1) and R^(6A2) are independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. R^(6A1) and R^(6A2) areoptionally joined to form a substituted or unsubstituted ring with thenitrogen to which they are attached. The ring formed by R^(6A1) andR^(6A2) optionally contains an additional ring heteroatom.

R^(6A3) is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.

Z³ is selected from —CR^(7A)R^(7B)—, ═CR^(7A)—, —C(O)—, —NR^(7C)—, ═N—,—O—, and —S—. R^(7C) is selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heteroaryl, andsubstituted or unsubstituted aryl. R^(7C) may also be selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted aryl.

R^(7A) and R^(7B) are independently selected from hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted aryl, —NR^(7A1)R^(7A2), and —OR^(7A3). R^(7A) andR^(7B) may also be independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aryl, —NR^(7A1)R^(7A2), and —OR^(7A3).

R^(7A1) and R^(7A2) are independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. R^(7A1) and R^(7A2) areoptionally joined to form a substituted or unsubstituted ring with thenitrogen to which they are attached. The ring formed by R^(7A1) andR^(7A2) optionally contains an additional ring heteroatom.

R^(7A3) is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments, R⁵, R^(6A), R^(6B), R^(6C), R^(6A1), R^(6A2),R^(6A3), R^(7A), R^(7B), R^(7C), R^(7A1), R^(7A2), R^(7A3) areindependently selected from substituted or unsubstituted (C₁-C₁₀) alkyl,substituted or unsubstituted 2-10 membered heteroalkyl, substituted orunsubstituted (C₃-C₇) cycloalkyl, substituted or unsubstituted 3-7membered heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

A variety of substituted or unsubstituted rings may be formed byconnecting some of the substituents described above. For example, R⁵ isoptionally joined with R^(6A) or R^(6C) to form a substituted orunsubstituted ring optionally including an additional ring heteroatom.In addition, R^(7A) is optionally joined with R^(6A) or R^(6C) to form asubstituted or unsubstituted ring optionally including an additionalring heteroatom. Still further, R^(7C) is optionally joined with R^(6A)or R^(6C) to form a substituted or unsubstituted ring optionallyincluding an additional ring heteroatom. In some related embodiments,where a ring is formed by R⁵ or R^(7A) as described above, the ring isselected from substituted or unsubstituted (C₃-C₇) cycloalkyl,substituted or unsubstituted 3-7 membered heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In some embodiments of the Formula (II) compound, Z¹ is —NR⁵—, Z² is═N—, and Z³ is ═CR^(7A)—. In a related embodiment, R^(7A) is hydrogenand R⁵ is a member selected from hydrogen, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted arylalkyl and substituted or unsubstitutedheteroarylalkyl. In a further related embodiment, R^(7A) is hydrogen andR⁵ is a member selected from substituted or unsubstituted alkyl andsubstituted or unsubstituted cycloalkyl.

R⁵ may also have the formula:

In Formula (VI), R^(5A) is a member selected from hydrogen, halogen,—OR^(5A1), —NR^(5A2)R^(5A3), —S(O₂)NR^(5A2)R^(5A3), CN, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl. The symbol m is an integer independentlyselected from 0 to 10. The symbol n is an integer independently selectedfrom 1 to 5.

R^(5A1) is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.R^(5A2) and R^(5A3) are independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. R^(5A2) and R^(5A3) areoptionally joined to form a substituted or unsubstituted ring with thenitrogen to which they are joined. The ring formed by R^(5A2) andR^(5A3) may be a substituted or unsubstituted (C₃-C₇) cycloalkyl,substituted or unsubstituted 3-7 membered heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(5A), R^(5A1), R^(5A2), R^(5A3) are independentlyselected from substituted or unsubstituted (C₁-C₁₀) alkyl, substitutedor unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted(C₃-C₇) cycloalkyl, substituted or unsubstituted 3-7 memberedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In some embodiments of Formula (VI), n is 1 and m is selected from 0and 1. In a related embodiment, n is 1 and m is 1. In another relatedembodiment, R^(5A1), R^(5A2) and R^(5A3) are hydrogen.

In another related embodiment, R⁵ and R^(7A) are hydrogen.

In yet another related embodiment, b is a bond.

In some embodiments of the Formula (II) compound, Z¹ is —NR⁵—, Z² is═CR^(6A)—, and Z³ is ═N—. In a related embodiment, R³ is a memberselected from hydrogen and substituted or unsubstituted aryl.

In an exemplary embodiment of the compound of Formula (I), the dashedline b is a bond; R¹ is substituted or unsubstituted benzyl; L¹ is abond; L² is a bond; and R² has the formula:

In this exemplary embodiment, R^(2G) is selected from hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. J is a substituted orunsubstituted ring selected from substituted or unsubstituted (C₃-C₇)cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. X is —S(O₂)—. The symbol t is an integer selected fro 0 to5.

In another embodiment, the compound of Formula (I) has the formula

In Formula (VII), L² and R² are as defined above in the discussion ofFormula (I). R^(1B) is as defined above in the discussion of Formula(III). R^(5A) is as defined above in the discussion of Formula (VI). L¹is selected from —CH₂— and —C(O)—.

In another exemplary embodiment, the compound of Formula (I) has theformula

In Formula (VIII), L² and R² are as defined above in the discussion ofFormula (I). R^(1B) is as defined above in the discussion of Formula(III).

In another exemplary embodiment, the compound of Formula (I) has theformula

In Formula (X), L² and R² are as defined above in the discussion ofFormula (I). R^(5A) is as defined above in the discussion of Formula(VI). -L¹-R¹ is selected from methyl (i.e. L¹ is a bond and R¹ ismethyl), —OR^(1A), —C(O)OR^(1A) (i.e. L¹ is a —C(O)— and R¹ is—OR^(1A)), —CH₂—OR^(1A), —(CH₂)₂—OR^(1A), —NR^(1C)R^(1D),—C(O)NR^(1C)R^(1D), —CH₂—NR^(1C)R^(1D), and —(CH₂)₂—NR^(1C)R^(1D).

In another exemplary embodiment, the compound of Formula (I) has theformula

In Formula (X), L¹, R¹, L² and R² are as defined above in the discussionof Formula (I). R^(6A) is as defined above in the discussion of Formula(II).

In another exemplary embodiment, the compound of Formula (I) has theformula

In Formula (XI), R^(1A), L² and R² are as defined above in thediscussion of Formula (I). R⁵ is as defined above in the discussion ofFormula (II). -L¹-R¹ is selected from methyl (i.e. L¹ is a bond and R¹is methyl), —OR^(1A), —C(O)OR^(1A) (i.e. L¹ is a —C(O)— and R¹ is—OR^(1A)), —CH₂—OR^(1A), —(CH₂)₂—OR^(1A), —C(O)NR^(1C)R^(1D),—CH₂—NR^(1C)R^(1D), and —(CH₂)₂—NR^(1C)R^(1D). In a related embodiment,-L¹-R¹ is selected from —CH₂—OR^(1A), and —CH₂—NR^(1C)R^(1D).

In an exemplary embodiment of the compound of Formula (II), the dashedline b is a bond; R¹ is substituted or unsubstituted benzyl; L¹ is abond; L² is a bond; Z′ is —NR⁵—; Z² is ═C^(6A)—, Z³ is ═N—; and R² hasthe formula:

In this exemplary embodiment, R^(2G) is selected from hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. J is a substituted orunsubstituted ring selected from substituted or unsubstituted (C₃-C₇)cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. The symbol t is 1. X is —S(O₂)—. R⁵ is hydrogen, alkyl,cycloalkyl, aryl or heteroaryl. R^(6A) is as defined in the descriptionof Formula (II).

In another exemplary embodiment, the compound of Formula (I) is selectedfrom one of the compounds set forth in Examples 15-23, 25, 28-29, or33-62.

In some embodiments of the compounds of Formulae (I)-(XI), eachsubstituted alkylene, substituted heteroalkylene, substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedarylalkyl, substituted heteroarylalkyl, and substituted ring structuresare substituted with a substituent group. In other embodiments of thecompounds of Formulae (I)-(XI), each substituted alkylene, substitutedheteroalkylene, substituted alkyl, substituted heteroalkyl, substitutedcycloalkyl, substituted heterocycloalkyl, substituted, substitutedheteroaryl, substituted alkylene, substituted heteroalkylene,substituted arylalkyl, and substituted heteroarylalkyl is substitutedwith a size-limited substituent group. In another embodiments of thecompounds of Formulae (I)-(XI), each substituted alkylene, substitutedheteroalkylene, substituted alkyl, substituted heteroalkyl, substitutedcycloalkyl, substituted heterocycloalkyl, substituted, substitutedheteroaryl, substituted alkylene, substituted heteroalkylene,substituted arylalkyl, and substituted heteroarylalkyl is substitutedwith a lower substituent group.

For example, where R¹, R^(1A), R^(1B), R^(1B1), R^(1B2), R^(1B3),R^(1B4), R^(1B5), R^(1B6), R^(1B7), R^(1B8), R^(1B9), R^(1B10), R^(1C),R^(1D), R^(2A), R^(2B3), R^(2C), R^(2D), R^(2G), R^(2I), R^(3A), R^(3B),R^(3C), R⁵, R^(5A), R^(5A1), R^(5A2), R^(5A3), R^(6A), R^(6B), R^(6C),R^(6A1), R^(6A2), R^(6A3), R^(7A), R^(7B), R^(7C), R^(7A1), R^(7A2),R^(7A3), R^(2A) are independently selected from a substituted alkylene,substituted heteroalkylene, substituted alkyl, substituted heteroalkyl,substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl,substituted heteroaryl, substituted arylalkyl, substitutedheteroarylalkyl, or form substituted ring structures, the designated Rgroup may be substituted with a substituent group. Alternatively, thedesignated R group may be substituted with a size-limited substituentgroup. In some embodiments, the designated R group is substituted with alower substituent group.

Likewise, where L¹ and L² are independently selected from a substitutedalkyleneor substituted heteroalkylene, L¹ and/or L² may substituted witha substituent group, size-limited substituent group, or lowersubstituent group. Where A is selected from substituted cycloalkyl,substituted heterocycloalkyl, substituted aryl, and substitutedheteroaryl, A may substituted with a substituent group, size-limitedsubstituent group, or lower substituent group.

II. Exemplary Syntheses

The compounds of the invention are synthesized by an appropriatecombination of generally well known synthetic methods. Techniques usefulin synthesizing the compounds of the invention are both readily apparentand accessible to those of skill in the relevant art. The discussionbelow is offered to illustrate certain of the diverse methods availablefor use in assembling the compounds of the invention. However, thediscussion is not intended to define the scope of reactions or reactionsequences that are useful in preparing the compounds of the presentinvention. Although some compounds in Schemes I-XVI may indicaterelative stereochemistry, the compounds may exist as a racemic mixtureor as either enantiomer. Compounds containing the double bond in theazadecalin core are designated Series A. Ring-saturated compounds aredesignated Series B.

In SchemeI, R^(1B), R², R^(2A), R^(2B), and R² are as defined above inthe discussion of the compounds of the present invention. R^(2M),R^(2J), and R^(2K) are independently selected from hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

Compounds 6A-11A are prepared as illustrated in SchemeI. A suitablyN-protected piperidone-2-carboxylic acid ester 1 is treated with a basesuch as sodium hydride, sodium ethoxide or potassium tert-butoxide in apolar solvent (e.g. N,N-dimethylformamide, ethanol, tert-butanol,dimethylsulfoxide, N-methyl-2-pyrrolidone and the like) followed by analkylating agent to afford the alkylated keto ester 2. SuitableN-protecting groups (Z) include benzyl and carbamate groups such astert-butoxycarbonyl (Boc) and the like. Typical alkylating agents areprimary, secondary or arylalkyl halides and are preferably benzylhalides in which the aromatic ring can be substituted with a R^(1B)group.

Keto ester 2 is hydrolyzed and decarboxylated by heating in a suitablesolvent such as aqueous methanol or ethanol in the presence of a strongacid (e.g. hydrochloric acid or sulfuric acid) to afford ketone 3. Thereaction is typically carried out at the reflux temperature of thesolvent mixture.

Ketone 3 is converted to enone 4 by a Robinson annelation reactioninvolving treatment of 3 with a base (e.g. potassium or sodiumalkoxides) in an alcohol solvent (e.g. methanol, ethanol, ortert-butanol) followed by addition of methylvinyl ketone (MVK). Thereaction is typically carried out at 0-25° C. This reaction can also becarried out with a nitrogen-containing base such as pyrrolidine,piperidine or morpholine in an aprotic solvent (e.g. benzene, toluene ordioxane) at reflux temperature followed by cooling and addition of MVK.

Enone 4 is prepared in optically active form when thenitrogen-containing base is an optical isomer of α-methylbenzylamine asdescribed in J. Med. Chem. 39: 2302 (1996). Alternatively, the Robinsonannelation can be carried out in an asymmetric manner with catalysis byan amino acid such as l-proline.

Removal of the N-protecting group Z from compound 4 is accomplishedunder standard conditions, such as treatment with a chloroformate andsubsequent hydrolysis when Z is benzyl, to afford amine 5A. Suitablechloroformates include methyl chloroformate, ethyl chloroformate andα-chloroethyl chloroformate. When Z is a group such as Boc, deprotectionis accomplished by treatment with a strong acid such as HCl in a proticsolvent (e.g., ethanol) or with trifluoroacetic acid.

Compound 6A may be prepared by alkylation of 5A with a primary orsecondary alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, orheteroarylalkyl halide. Alternatively, 6A may be prepared by reductivealkylation of 5A with the requisite aldehyde in the presence of areducing agent such as sodium borohydride or sodium cyanoborohydride inan inert solvent (e.g. 1,2-dichloroethane).

Compound 7A where R² is aryl or heteroaryl may be prepared by treatmentof 5A with an aryl, heteroaryl halide, or boronic acid in the presenceof a copper or palladium catalyst (e.g., copper (II) acetate, palladium(II) chloride) and a base such as triethylamine.

Compound 8A may be prepared by acylation of 5A with a primary, secondaryor tertiary alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, orheteroarylalkyl carbonyl halide in a suitable protic or aprotic solventin the presence of a base such as sodium hydroxide, triethylamine andthe like. Alternatively, 8A may be prepared by coupling of amine 5A withthe requisite carboxylic acid in the presence of a suitable couplingagent such as N,N-dicyclohexylcarbodiimide.

Compound 9A where R^(2K) is hydrogen may be prepared by treatment of 5Awith a primary, secondary or tertiary alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, or heteroarylalkyl isocyanate in an inertsolvent (e.g. toluene, dichloromethane, 1,2-dichloroethane or dioxane).When R^(2K) is a group other than hydrogen, compound 9A may be preparedby treatment of 5A with the carbamoyl halide R^(2J)R^(2K)NC(O)X (where Xis Cl, Br, F) in an inert solvent (e.g. toluene, dichloromethane,1,2-dichloroethane or dioxane) in the presence of a base such astriethylamine.

Compound 10A is prepared by treatment of 5A with a primary, secondary ortertiary alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, orheteroarylalkyl sulfonyl halide in an inert solvent (e.g. toluene,dichloromethane, 1,2-dichloroethane or dioxane) in the presence of abase such as triethylamine.

Compound 11A is prepared by treatment of 5A with the sulfamoyl halideR^(2B)R^(2C)NSO₂X (where X is Cl, Br, or F) in an inert solvent (e.g.toluene, dichloromethane, 1,2-dichloroethane or dioxane) in the presenceof a base such as triethylamine.

In SchemeII, R^(1B), R², R^(2A), R^(2B), R^(2C), R^(2M), R^(2J), andR^(2K) are as defined above in SchemeI.

Compounds 6B-11B are similarly prepared from saturated ketone 5B(SchemeII) according to the reactions previously described in SchemeI.One skilled in the art will immediately recognize that compound 5B canalso exist as the cis isomer. SchemeII exemplifies the preparation ofthe trans isomers of compounds 6B-11B. However, the reaction scheme isequally applicable to the preparation of the corresponding cis isomers.

Reduction of enone 4 to saturated ketone 5B is accomplished by catalytichydrogenation using a catalyst such as palladium or platinum catalyst inan inert solvent, such as tetrahydrofuran or an alcohol such as ethanol.Alternatively, 5B can be prepared by treatment of 4 with a dissolvingmetal, such as lithium, in liquid ammonia.

In SchemeIII, R^(1B), R², R^(5A), R^(6C), and L² are as defined above inthe discussion of the compounds of the present invention. R^(6D) isselected from hydrogen, halogen, —OH, —NH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

Compounds 13A,B-17A,B are prepared as described in SchemeIII. Treatmentof ketones 6A,B-11A,B with a formylating agent such as ethyl formate inthe presence of a base such as sodium methoxide or sodium hydride in anaprotic solvent such as toluene affords hydroxymethylene derivatives12A,B. Treatment of 12A,B with hydrazine in an alcohol solvent withheating to the reflux temperature of the mixture yields pyrazoles 13A,B.Treatment of 12A,B with an alkyl hydrazine under similar conditionsaffords pyrazoles 14A,B. Treatment of 12A,B with an aryl hydrazineaffords the regioisomeric pyrazoles 15A,B. Treatment of 12A,B withhydroxylamine in a solvent such as ethyl acetate in the presence ofacetic acid affords isoxazoles 16A,B. Pyrimidines 17A,B are prepared bytreatment of 12A,B with guanidine (R^(6D)=NH₂) or an amidine(R^(6D)=alkyl or aryl) in an alcohol solvent in the presence of a basesuch as sodium ethoxide.

Compounds 19A,B-21A,B are prepared as shown in SchemeIV. Bromination ofketones 6A,B-11A,B by conventional methods such as treatment withcuprous bromide or by treatment of 6A,B-11A,B with a strong base, suchas lithium diisopropylamide, and a brominating agent such asN-bromosuccinimide in a solvent such as tetrahydrofuran, affords bromoderivatives 18A,B. Thiazoles 19A,B are prepared by treatment of 18A,Bwith thiourea (R^(6A)=NH₂) or a thioamide (R^(6A)=alkyl or aryl) in asolvent such as acetonitrile. Imidazoles 22A,B are prepared by treatmentof 18A,B with guanidine (R^(6A)=NH₂) or an amidine (R^(6A)=alkyl oraryl) in an alcohol solvent in the presence of a base such as sodiumethoxide. Oxazoles 20A,B are prepared by heating 18A,B with a primaryamide in an alcohol solvent such as ethanol. Imidazolones 21A,B areprepared by heating 18A,B with a N,N′-disubstituted urea in an alcoholsolvent such as ethanol.

In SchemeIV, R^(1B), L², R², R⁵, R^(6A), and R^(7C) are as defined abovein the discussion of the compounds of the present invention.

Substituted imidazoles 25A,B can also be prepared as shown in Scheme V.In Scheme V, L¹, L², R¹, R² and R^(6A) are as defined above in thecompounds of the present invention. Compounds 24A,B may be prepared fromketones 23A,B by treatment with manganese acetate in a suitable inertsolvent such as toluene or THF. Conversion of compounds 24A,B tocompounds 25A,B is accomplished by treatment with copper^(II) acetateand ammonia and a suitable aldehyde (for example where R^(6A) is methyl,the ketone is acetaldehyde) in a protic solvent such as methanol orethanol.

The group R^(1B) in compounds 27A,B-30A,B can be modified prior tosynthesis of the compounds according to Schemes III and IV, asexemplified in Scheme VI. Thus, brominated derivatives, such as 26A,Bcan be converted to amino derivatives 30A,B by conversion to the(bis-pinacolato)diboron derivative followed by copper-catalyzedamination. Similarly, the bromo derivative may be converted to arylethers 29A,B by metal-catalyzed ether formation or to amide derivatives28A,B by palladium-catalyzed carbonylation/amidation procedures.Derivatives 27A,B in which R^(1B) is heteroaryl can be prepared bytreatment of 26A,B with a heteroarylboronic acid in the presence of apalladium catalyst.

In Scheme VI, R^(1B) is heteroaryl and R^(1B1), R^(1B2), R^(1B3),R^(1B4), R^(1B5), L², and R² are as defined above in the discussion ofthe compounds of the present invention.

Alternatively, the group R^(1B) in compounds 13A,B-17A,B and 19A,B-22A,Bcan be modified subsequent to synthesis of the compounds according toSchemes III and IV, as exemplified in Scheme VII for the synthesis ofpyrazole derivatives 32A,B-35A,B. Thus, brominated derivatives, such as31A,B can be converted to amino derivatives 35A,B by conversion to the(bis-pinacolato)diboron derivative followed by copper-catalyzedamination. Similarly, the bromo derivative may be converted to arylethers 34A,B by metal-catalyzed ether formation or to amide derivativesby palladium-catalyzed carbonylation/amidation procedures. Derivatives32A,B in which R^(1B) is heteroaryl can be prepared by treatment of31A,B with a heteroarylboronic acid in the presence of a palladiumcatalyst.

In Scheme VII, R^(1B) is heteroaryl and R^(1B1), R^(1B2), R^(1B3),R^(1B4), R^(1B5), L², and R² are as defined above in the discussion ofthe compounds of the present invention.

It will be appreciated by one skilled in the art that the routesillustrated in Schemes I-IV and VI, VII wherein L¹-R¹ represents asubstituted benzyl group may also be applied to compounds in which L¹-R¹represents an alkyl substituted lower alkyl group, for example a methylgroup, as described in Scheme VIII. Either enantionmer of enone 36A, inwhich L²-R² represents a benzyl group, can be prepared by Robinsonannelation when the nitrogen-containing base is an optical isomer ofα-methylbenzylamine as described in J. Med. Chem. 39: 2302 (1996).Compounds 38A,B-42A,B are prepared from 37A,B according to theprocedures described for the preparation of the compounds in SchemeIII.

Pyrazoles 44A,B, in which R⁵ is alkyl, substituted alkyl, cycloalkyl orsubstituted cycloalkyl can be prepared by an alternative procedure asdescribed in SchemeIX. It will be appreciated by one skilled in the artthat these compounds are regioisomeric with pyrazoles exemplified bycompounds 14A,B and 39A,B in Scheme VIII. The preparation of 44A,Binvolves reaction of 43A,B with a Boc-protected hydrazine, followed bytreatment with a strong acid, such as trifluoroacetic, hydrochloric acidand the like.

Compounds 49A-53A are prepared as described in Scheme X. In Scheme X,R⁵, R^(1A), R^(1C), R^(1D), L² and R² are as defined above in thecompounds of the present invention. In Scheme X, L²-R² can be replacedby a suitable protecting group, such as BOC or benzyl, to facilitate thesynthesis. Keto-ester 45 is converted directly to enone 47A by aRobinson annelation reaction involving treatment of 45 with a base (e.g.potassium or sodium alkoxides) in an alcohol solvent (e.g. methanol,ethanol, or tert-butanol) followed by addition of methylvinyl ketone(MVK). The reaction is typically carried out at 0-25° C.

Alternatively, compounds 47A can be prepared in optically active form.The suitably N-protected piperidone-2-carboxylic acid ester 45 is heatedwith an optically active nitrogen-containing base (as described in J.Med. Chem. 39: 2302 (1996)) such as (R)-(+)-α-methylbenzylamine or(S)-2-amino-N,N-diethyl-3-methyl-butyramide, in a suitable solvent (suchas toluene, benzene or dioxane) under dehydrating conditions(concentrated HCl, molecular sieves or Dean-Stark trap). Theintermediate enamine is then treated with methylvinyl ketone in anapolar solvent such as acetone in the presence of copper^(II) acetate toafford the optically active methylvinyl ketone adduct 46. SuitableN-protecting groups (Z) include benzyl and carbamate groups such astert-butoxycarbonyl (Boc) and the like.

Optically active ketone 46 is converted to enone 47A by treatment with abase (e.g. potassium or sodium alkoxides) in an alcohol solvent (e.g.methanol, ethanol, or tert-butanol) or by addition of anitrogen-containing base such as pyrrolidine, piperidine or morpholinein an aprotic solvent (e.g. benzene, toluene or dioxane).

Treatment of ketones 47A with a formylating agent such as ethyl formateor trifluoroethyl formate, as described for example in Organic Letters,1 (7), 989, (1999), in the presence of a base such as sodium methoxide,LDA or sodium hydride in an aprotic solvent such as toluene affordshydroxymethylene derivatives 48A. Treatment of 48A with hydrazine, aprotected alkyl hydrazine (as in SchemeIX) or an aryl hydrazine in analcohol solvent or acetic acid with heating to the reflux temperature ofthe mixture affords pyrazoles 49A.

Alcohols 50A are prepared by treatment of ester 49A with a reducingagent such as DIBAL-H, LiAlH₄ or RED-AL in an inert solvent such as THF,benzene or toluene.

Alcohols 50A are converted into ether derivatives 51A by treatment witha base (e.g. sodium hydride) in an aprotic solvent (e.g.tetrahydrofuran, N,N-dimethylformamide) followed by addition of asubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heterocycylalkyl halide.

Aldehyde intermediate 52A is prepared by reduction of ester 49A with areducing agent such as DIBAL-H in toluene or dimethoxyethanol or sodiumborohydride in ethanol or diglyme. Alternatively, compounds 52A areprepared from alcohols 50A by treatment with an oxidizing agent (e.g.chromium (VI) reagents such as pyridinium chlorochromate and pyridiniumdichromate) in an aprotic solvent (e.g. dichloromethane); or using theSwern oxidation method (oxalyl chloride and dimethyl sulfoxide followedby addition of an organic base such as triethylamine).

Compounds 53A are prepared by reductive amination of aldehydes 52A withammonia, a secondary amine, or a tertiary amine. The reaction is carriedout by treatment of 52A with the amino component and a reducing agent(e.g. hydrogen, sodium borohydride or sodium cyanoborohydride) in asolvent such as tetrahydrofuran, ethanol, 1,2-dichloroethane and thelike.

Saturated compounds 49B-53B are prepared as described in Scheme XI. Itwill be appreciated that Scheme XI exemplifies the synthesis of pyrazolederivatives; however, the synthesis of other heterocyclic examples suchas those shown in Schemes III, IV and V can proceed analogously.Reduction of enone 47A to saturated ketone 47B is accomplished bycatalytic hydrogenation using a catalyst such as palladium or platinumcatalyst in an inert solvent, such as tetrahydrofuran or an alcohol suchas ethanol, or using Raney nickel with hydrogen.

In Scheme XII, R⁵, R^(1C), R^(1D), L² and R² are as defined above in thecompounds of the present invention. Compounds 54A,B may be prepared from49A,B by hydrolysis of the ester using aqueous solutions of lithiumhydroxide or sodium hydroxide in alcoholic solvents such as ethanol ormethanol. Amides 55A,B may be prepared from 54A,B and an amine usingstandard methods of amide bond formation, for example, EDC or HATU withan organic base such as diisopropylethylamine or triethylamine in aninert solvent such as dichloromethane.

In Scheme XIII, R⁵, L², R¹ and R² are as defined above in the compoundsof the present invention.

Compounds 56A,B may be prepared from aldehydes 52A,B by treatment with asuitable organometallic species, such as a Grignard reagent, anorganocerium reagent or an organozinc reagent, in a solvent such asether, THF or a similar aprotic solvent. Compounds 57A,B may be preparedfrom 56A,B using, for example, Swern oxidation conditions or anoxidizing agent such as MnO₂ in an inert solvent such asdichloromethane.

In Scheme XIV, R⁵, L², R^(1A), R^(1C), R^(1D) and R² are as definedabove in the compounds of the present invention.

Thioketene acetals 58A,B may be prepared from acids 54A,B by treatmentwith 2-trimethylsilyl-1,3-dithiane and n-butyl lithium in an aproticsolvent such as THF. Typically, the chemistry is performed at −78° C.Esters 59A,B are formed by the treatment of 58A,B with mercury^(II)chloride and perchloric acid in methanol.

Reduction of the ester in compounds 59A,B is achieved with a reducingagents such as DIBAL-H, LiAlH₄ or RED-AL in an inert solvent such asTHF, benzene or toluene to afford alcohols 60A,B. Alcohols 60A,B areconverted into ether derivatives 61A,B by treatment with a base (e.g.sodium hydride) in an aprotic solvent (e.g. tetrahydrofuran,N,N-dimethylformamide) followed by addition of a substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheterocycylalkyl halide.

Aldehydes 62A,B are prepared by reduction of esters 59A,B with areducing agent such as DIBAL-H in toluene or dimethoxyethanol or sodiumborohydride in ethanol or diglyme. Alternatively, compounds 62A,B areprepared from alcohols 60A,B by oxidation with an oxidizing agent (e.g.chromium (VI) reagents such as pyridinium chlorochromate and pyridiniumdichromate) in an aprotic solvent (e.g. dichloromethane); or using theSwern oxidation method (oxalyl chloride and dimethyl sulfoxide followedby addition of an organic base such as triethylamine).

Amines 63A,b are prepared by reductive amination of aldehydes 62A,B withammonia, a secondary amine, or a tertiary amine. The reaction is carriedout by treatment of 62A,B with the amine component and a reducing agent(e.g. hydrogen, sodium borohydride or sodium cyanoborohydride) in asolvent such as tetrahydrofuran, ethanol, 1,2-dichloroethane and thelike. Amines 63A,B could also be prepared by conversion of the alcoholgroup in 60A,B to a leaving group, such as a sulfonate or halide,followed by displacement of the leaving group with an amine.

Saturated compounds 44B can also prepared as described in Scheme XV. Itwill be appreciated that Scheme XV exemplifies the synthesis of pyrazolederivatives; however, the synthesis of other heterocyclic examples suchas those shown in Schemes III, IV and V can proceed analogously.Reduction of enone 44A to saturated ketone 44B is accomplished bycatalytic hydrogenation using a catalyst such as palladium or platinumcatalyst in an inert solvent, such as tetrahydrofuran or an alcohol suchas ethanol, or using Raney nickel with hydrogen.

Compounds 44A,B can also be prepared as shown in Scheme XVI byintroducing the grouping L²-R² into intermediates 65A,B which can beprepared from a protected amine of the type 64A,B. The conditions andprocedures for these conversions are the same as those described for thepreparations in Schemes I and II.

III. Assays and Methods for Modulating Glucocorticoid Receptor Activity

The compounds of the present invention can be tested for theirantiglucocorticoid properties. Methods of assaying compounds capable ofmodulating glucocorticoid receptor activity are presented herein.Typically, compounds of the current invention are capable of modulatingglucocorticoid receptor activity by selectively binding to the GR or bypreventing GR ligands from binding to the GR. In some embodiments, thecompounds exhibit little or no cytotoxic effect. Therefore, exemplaryassays disclosed herein may test the ability of compounds to (1) bind tothe GR; (2) selectively bind to the GR; (3) prevent GR ligands frombinding to the GR; (4) modulate the activity of the GR in a cellularsystem; and/or (5) exhibit non-cytotoxic effects.

Binding Assays

In some embodiments, GR modulators are identified by screening formolecules that compete with a ligand of GR, such as dexamethasone. Thoseof skill in the art will recognize that there are a number of ways toperform competitive binding assays. In some embodiments, GR ispre-incubated with a labeled GR ligand and then contacted with a testcompound. This type of competitive binding assay may also be referred toherein as a binding displacement assay. Alteration (e.g., a decrease) ofthe quantity of ligand bound to GR indicates that the molecule is apotential GR modulator. Alternatively, the binding of a test compound toGR can be measured directly with a labeled test compound. This lattertype of assay is called a direct binding assay.

Both direct binding assays and competitive binding assays can be used ina variety of different formats. The formats may be similar to those usedin immunoassays and receptor binding assays. For a description ofdifferent formats for binding assays, including competitive bindingassays and direct binding assays, see Basic and Clinical Immunology 7thEdition (D. Stites and A. Ten ed.) 1991; Enzyme Immunoassay, E. T.Maggio, ed., CRC Press, Boca Raton, Fla. (1980); and “Practice andTheory of Enzyme Immunoassays,” P. Tijssen, Laboratory Techniques inBiochemistry and Molecular Biology, Elsevier Science Publishers B.V.Amsterdam (1985), each of which is incorporated herein by reference.

In solid phase competitive binding assays, for example, the samplecompound can compete with a labeled analyte for specific binding siteson a binding agent bound to a solid surface. In this type of format, thelabeled analyte can be a GR ligand and the binding agent can be GR boundto a solid phase. Alternatively, the labeled analyte can be labeled GRand the binding agent can be a solid phase GR ligand. The concentrationof labeled analyte bound to the capture agent is inversely proportionalto the ability of a test compound to compete in the binding assay.

Alternatively, the competitive binding assay may be conducted in liquidphase, and any of a variety of techniques known in the art may be usedto separate the bound labeled protein from the unbound labeled protein.For example, several procedures have been developed for distinguishingbetween bound ligand and excess bound ligand or between bound testcompound and the excess unbound test compound. These includeidentification of the bound complex by sedimentation in sucrosegradients, gel electrophoresis, or gel isoelectric focusing;precipitation of the receptor-ligand complex with protamine sulfate oradsorption on hydroxylapatite; and the removal of unbound compounds orligands by adsorption on dextran-coated charcoal (DCC) or binding toimmobilized antibody. Following separation, the amount of bound ligandor test compound is determined.

Alternatively, a homogenous binding assay may be performed in which aseparation step is not needed. For example, a label on the GR may bealtered by the binding of the GR to its ligand or test compound. Thisalteration in the labeled GR results in a decrease or increase in thesignal emitted by label, so that measurement of the label at the end ofthe binding assay allows for detection or quantitation of the GR in thebound state. A wide variety of labels may be used. The component may belabeled by any one of several methods. Useful radioactive labels includethose incorporating ³H, ¹²⁵I, ³⁵S, ¹⁴C, or ³²P. Useful non-radioactivelabels include those incorporating fluorophores, chemiluminescentagents, phosphorescent agents, electrochemiluminescent agents, and thelike. Fluorescent agents are especially useful in analytical techniquesthat are used to detect shifts in protein structure such as fluorescenceanisotropy and/or fluorescence polarization. The choice of label dependson sensitivity required, ease of conjugation with the compound,stability requirements, and available instrumentation. For a review ofvarious labeling or signal producing systems which may be used, see U.S.Pat. No. 4,391,904, which is incorporated herein by reference in itsentirety for all purposes. The label may be coupled directly orindirectly to the desired component of the assay according to methodswell known in the art.

For competitive binding assays, the amount of inhibition may be deteimined using the techniques disclosed herein. The amount of inhibition ofligand binding by a test compound depends on the assay conditions and onthe concentrations of ligand, labeled analyte, and test compound thatare used. In an exemplary embodiment, a compound is said to be capableof inhibiting the binding of a GR ligand to a GR in a competitivebinding assay if the inhibition constant (K_(i)) is less than 5 μM usingthe assay conditions presented in Example 63. In another exemplaryembodiment, a compound is said to be capable of inhibiting the bindingof a GR ligand to a GR in a competitive binding assay if the K_(i) isless than 1 μM using the assay conditions presented in Example 63. Inanother exemplary embodiment, a compound is said to be capable ofinhibiting the binding of a GR ligand to a GR in a competitive bindingassay if the K_(i) is less than 100 nM using the assay conditionspresented in Example 63. In another exemplary embodiment, a compound issaid to be capable of inhibiting the binding of a GR ligand to a GR in acompetitive binding assay if the K_(i) is less than 10 nM using theassay conditions presented in Example 63. In another exemplaryembodiment, a compound is said to be capable of inhibiting the bindingof a GR ligand to a GR in a competitive binding assay if the K_(i) isless than 1 nM using the assay conditions presented in Example 63. Inanother exemplary embodiment, a compound is said to be capable ofinhibiting the binding of a GR ligand to a GR in a competitive bindingassay if the K_(i) is less than 100 pM using the assay conditionspresented in Example 63. In another exemplary embodiment, a compound issaid to be capable of inhibiting the binding of a GR ligand to a GR in acompetitive binding assay if the K_(i) is less than 10 pM using theassay conditions presented in Example 63.

High-throughput screening methods may be used to assay a large number ofpotential modulator compounds. Such “compound libraries” are thenscreened in one or more assays, as described herein, to identify thoselibrary members (particular chemical species or subclasses) that displaya desired characteristic activity. Preparation and screening of chemicallibraries is well known to those of skill in the art. Devices for thepreparation of chemical libraries are commercially available (see, e.g.,357 MPS, 390 MPS, Advanced Chem Tech, Louisville Ky., Symphony, Rainin,Woburn, Mass., 433A Applied Biosystems, Foster City, Calif., 9050 Plus,Millipore, Bedford, Mass.).

Cell-Based Assays

Cell-based assays involve whole cells or cell fractions containing GR toassay for binding or modulation of activity of GR by a compound of thepresent invention. Exemplary cell types that can be used according tothe methods of the invention include, e.g., any mammalian cellsincluding leukocytes such as neutrophils, monocytes, macrophages,eosinophils, basophils, mast cells, and lymphocytes, such as T cells andB cells, leukemias, Burkitt's lymphomas, tumor cells (including mousemammary tumor virus cells), endothelial cells, fibroblasts, cardiaccells, muscle cells, breast tumor cells, ovarian cancer carcinomas,cervical carcinomas, glioblastomas, liver cells, kidney cells, andneuronal cells, as well as fungal cells, including yeast. Cells can beprimary cells or tumor cells or other types of immortal cell lines. Ofcourse, GR can be expressed in cells that do not express an endogenousversion of GR.

In some cases, fragments of GR, as well as protein fusions, can be usedfor screening. When molecules that compete for binding with GR ligandsare desired, the GR fragments used are fragments capable of binding theligands (e.g., dexamethasone). Alternatively, any fragment of GR can beused as a target to identify molecules that bind GR. GR fragments caninclude any fragment of, e.g., at least 20, 30, 40, 50 amino acids up toa protein containing all but one amino acid of GR. Typically,ligand-binding fragments will comprise transmembrane regions and/or mostor all of the extracellular domains of GR.

In some embodiments, signaling triggered by GR activation is used toidentify GR modulators. Signaling activity of GR can be determined inmany ways. For example, downstream molecular events can be monitored todetermine signaling activity. Downstream events include those activitiesor manifestations that occur as a result of stimulation of a GRreceptor. Exemplary downstream events useful in the functionalevaluation of transcriptional activation and antagonism in unalteredcells include upregulation of a number of glucocorticoid responseelement (GRE)-dependent genes (PEPCK, tyrosine amino transferase,aromatase). In addition, specific cell types susceptible to GRactivation may be used, such as osteocalcin expression in osteoblastswhich is downregulated by glucocorticoids; primary hepatocytes whichexhibit glucocorticoid mediated upregulation of PEPCK andglucose-6-phosphate (G-6-Pase)). GRE-mediated gene expression has alsobeen demonstrated in transfected cell lines using well-knownGRE-regulated sequences (e.g. the mouse mammary tumor virus promoter(MMTV) transfected upstream of a reporter gene construct). Examples ofuseful reporter gene constructs include luciferase (luc), alkalinephosphatase (ALP) and chloramphenicol acetyl transferase (CAT). Thefunctional evaluation of transcriptional repression can be carried outin cell lines such as monocytes or human skin fibroblasts. Usefulfunctional assays include those that measure IL-1beta stimulated IL-6expression; the downregulation of collagenase, cyclooxygenase-2 andvarious chemokines (MCP-1, RANTES); or expression of genes regulated byNFkB or AP-1 transcription factors in transfected cell-lines. An exampleof a cell-based assay measuring gene transcription is presented inExample 65.

Typically, compounds that are tested in whole-cell assays are alsotested in a cytotoxicity assay. Cytotoxicity assays are used todetermine the extent to which a perceived modulating effect is due tonon-GR binding cellular effects. In an exemplary embodiment, thecytotoxicity assay includes contacting a constitutively active cell withthe test compound. Any decrease in cellular activity indicates acytotoxic effect. An exemplary cytotoxicity assay is presented inExample 66.

Specificity

The compounds of the present invention may be subject to a specificityassay (also referred to herein as a selectivity assay). Typically,specificity assays include testing a compound that binds GR in vitro orin a cell-based assay for the degree of binding to non-GR proteins.Selectivity assays may be performed in vitro or in cell based systems,as described above. GR binding may be tested against any appropriatenon-GR protein, including antibodies, receptors, enzymes, and the like.In an exemplary embodiment, the non-GR binding protein is a cell-surfacereceptor or nuclear receptor. In another exemplary embodiment, thenon-GR protein is a steroid receptor, such as estrogen receptor,progesterone receptor, androgen receptor, or mineralocorticoid receptor.An exemplary specificity assay is presented in Example 64.

Methods of Modulating GR Activity

In another aspect, the present invention provides methods of modulatingglucocorticoid receptor activity using the techniques described above.In an exemplary embodiment, the method includes contacting a GR with aneffective amount of a compound of the present invention, such as thecompound of Formula (I), and detecting a change in GR activity.

In an exemplary embodiment, the GR modulator is an antagonist of GRactivity (also referred to herein as “a glucocorticoid receptorantagonist”). A glucocorticoid receptor antagonist, as used herein,refers to any composition or compound which partially or completelyinhibits (antagonizes) the binding of a glucocorticoid receptor (GR)agonist (e.g. cortisol and synthetic or natural cortisol analog) to a GRthereby inhibiting any biological response associated with the bindingof a GR to the agonist.

In a related embodiment, the GR modulator is a specific glucocorticoidreceptor antagonist. As used herein, a specific glucocorticoid receptorantagonist refers to a composition or compound which inhibits anybiological response associated with the binding of a GR to an agonist bypreferentially binding to the GR rather than another nuclear receptor(NR). In some embodiments, the specific glucocorticoid receptorantagonist binds preferentially to GR rather than the mineralocorticoidreceptor (MR) or progesterone receptor (PR). In an exemplary embodiment,the specific glucocorticoid receptor antagonist binds preferentially toGR rather than the mineralocorticoid receptor (MR). In another exemplaryembodiment, the specific glucocorticoid receptor antagonist bindspreferentially to GR rather than the progesterone receptor (PR).

In a related embodiment, the specific glucocorticoid receptor antagonistbinds to the GR with an association constant (K_(d)) that is at least10-fold less than the K_(d) for the NR. In another embodiment, thespecific glucocorticoid receptor antagonist binds to the GR with anassociation constant (K_(d)) that is at least 100-fold less than theK_(d) for the NR. In another embodiment, the specific glucocorticoidreceptor antagonist binds to the GR with an association constant (K_(d))that is at least 1000-fold less than the K_(d) for the NR.

In an exemplary embodiment, the present invention provides a method oftreating a disorder or condition. The method includes modulating aglucocorticoid receptor by administering to a subject in need of suchtreatment, an effective amount of a compound of the present invention.

Methods of treating a disorder or condition through antagonizing aglucocorticoid receptor are also provided. The method includesadministering to a subject in need of such treatment, an effectiveamount of a compound of the present invention.

In other embodiments, a method of modulating a glucocorticoid receptoris provided. The method includes the steps of contacting aglucocorticoid receptor with an effective amount of a compound of thepresent invention and detecting a change in the activity of theglucocorticoid receptor.

IV. Pharmaceutical Compositions of Glucocorticoid Receptor Modulators

In another aspect, the present invention provides pharmaceuticalcompositions including a pharmaceutically acceptable excipient and acompound of the present invention, such as the compound of Formula (I)provided above.

The compounds of the present invention can be prepared and administeredin a wide variety of oral, parenteral and topical dosage forms. Oralpreparations include tablets, pills, powder, dragees, capsules, liquids,lozenges, gels, syrups, slurries, suspensions, etc., suitable foringestion by the patient. The compounds of the present invention canalso be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. Also, the compounds described herein can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the present invention can be administered transdermally.The GR modulators of this invention can also be administered by inintraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations (forexamples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol.35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111,1995). Accordingly, the present invention also provides pharmaceuticalcompositions including a pharmaceutically acceptable carrier orexcipient and either a compound of Formula (I), or a pharmaceuticallyacceptable salt of a compound of Formula (I).

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material. Details ontechniques for formulation and administration are well described in thescientific and patent literature, see, e.g., the latest edition ofRemington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa.(“Remington's”).

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets preferably contain from 5% or 10% to 70% of theactive compound. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

Suitable solid excipients are carbohydrate or protein fillers include,but are not limited to sugars, including lactose, sucrose, mannitol, orsorbitol; starch from corn, wheat, rice, potato, or other plants;cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, orsodium carboxymethylcellulose; and gums including arabic and tragacanth;as well as proteins such as gelatin and collagen. If desired,disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can contain GRmodulator mixed with a filler or binders such as lactose or starches,lubricants such as talc or magnesium stearate, and, optionally,stabilizers. In soft capsules, the GR modulator compounds may bedissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin, or liquid polyethylene glycol with or without stabilizers.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethylene oxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensationproduct of ethylene oxide with a partial ester derived from fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).The aqueous suspension can also contain one or more preservatives suchas ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can be formulated by suspending a GR modulator in avegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin; or a mixture of these.The oil suspensions can contain a thickening agent, such as beeswax,hard paraffin or cetyl alcohol. Sweetening agents can be added toprovide a palatable oral preparation, such as glycerol, sorbitol orsucrose. These formulations can be preserved by the addition of anantioxidant such as ascorbic acid. As an example of an injectable oilvehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Thepharmaceutical formulations of the invention can also be in the form ofoil-in-water emulsions. The oily phase can be a vegetable oil or amineral oil, described above, or a mixture of these. Suitableemulsifying agents include naturally-occurring gums, such as gum acaciaand gum tragacanth, naturally occurring phosphatides, such as soybeanlecithin, esters or partial esters derived from fatty acids and hexitolanhydrides, such as sorbitan mono-oleate, and condensation products ofthese partial esters with ethylene oxide, such as polyoxyethylenesorbitan mono-oleate. The emulsion can also contain sweetening agentsand flavoring agents, as in the formulation of syrups and elixirs. Suchformulations can also contain a demulcent, a preservative, or a coloringagent.

The GR modulators of the invention can be delivered by transdermally, bya topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols.

The GR modulators of the invention can also be delivered as microspheresfor slow release in the body. For example, microspheres can beadministered via intradermal injection of drug-containing microspheres,which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym.Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations(see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres fororal administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). Both transdermal and intradermal routes afford constant deliveryfor weeks or months.

The GR modulator pharmaceutical formulations of the invention can beprovided as a salt and can be formed with many acids, including but notlimited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic,succinic, etc. Salts tend to be more soluble in aqueous or otherprotonic solvents that are the corresponding free base forms. In othercases, the preparation may be a lyophilized powder in 1 mM-50 mMhistidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5,that is combined with buffer prior to use

In another embodiment, the GR modulator formulations of the inventionare useful for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the GR modulator dissolved in a pharmaceutically acceptablecarrier. Among the acceptable vehicles and solvents that can be employedare water and Ringer's solution, an isotonic sodium chloride. Inaddition, sterile fixed oils can conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid can likewise be used in the preparation ofinjectables. These solutions are sterile and generally free ofundesirable matter. These formulations may be sterilized byconventional, well known sterilization techniques. The formulations maycontain pharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions such as pH adjusting and bufferingagents, toxicity adjusting agents, e.g., sodium acetate, sodiumchloride, potassium chloride, calcium chloride, sodium lactate and thelike. The concentration of GR modulator in these formulations can varywidely, and will be selected primarily based on fluid volumes,viscosities, body weight, and the like, in accordance with theparticular mode of administration selected and the patient's needs. ForIV administration, the formulation can be a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension can be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation can also be a sterile injectablesolution or suspension in a nontoxic parenterally-acceptable diluent orsolvent, such as a solution of 1,3-butanediol.

In another embodiment, the GR modulator formulations of the inventioncan be delivered by the use of liposomes which fuse with the cellularmembrane or are endocytosed, i.e., by employing ligands attached to theliposome, or attached directly to the oligonucleotide, that bind tosurface membrane protein receptors of the cell resulting in endocytosis.By using liposomes, particularly where the liposome surface carriesligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of the GRmodulator into the target cells in vivo. (See, e.g., Al-Muhammed, J.Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

V. Methods for Treating Conditions Mediated by Glucocorticoid Receptors

In another aspect, the present invention provides a method for thetreatment of a disorder or condition through modulation of aglucocorticoid receptor. In this method, a subject in need of suchtreatment is administered an effective amount of a compound of thepresent invention. The amount is effective in modulating theglucocorticoids receptor.

A variety of disease states are capable of being treated withglucocorticoid receptor modulators of the present invention. Exemplarydisease states include major psychotic depression, mild cognitiveimpairment, psychosis, dementia, hyperglycemia, stress disorders,antipsychotic induced weight gain, delirium, cognitive impairment indepressed patients, cognitive deterioration in individuals with Down'ssyndrome, psychosis associated with interferon-alpha therapy, chronicpain (e.g. pain associate with gastroesophageal reflux disease),postpartum psychosis, postpartum depression, neurological disorders inpremature infants, migraine headaches, obesity, diabetes, cardiovasculardisease, hypertension, Syndrome X, depression, anxiety, glaucoma, humanimmunodeficiency virus (HIV) or acquired immunodeficiency syndrome(AIDS), neurodegeneration (e.g. Alzheimer's disease and Parkinson'sdisease), cognition enhancement, Cushing's Syndrome, Addison's Disease,osteoporosis, frailty, inflammatory diseases (e.g., osteoarthritis,rheumatoid arthritis, asthma and rhinitis), adrenal function-relatedailments, viral infection, immunodeficiency, immunomodulation,autoimmune diseases, allergies, wound healing, compulsive behavior,multi-drug resistance, addiction, psychosis, anorexia, cachexia,post-traumatic stress syndrome post-surgical bone fracture, medicalcatabolism, and muscle frailty. The methods of treatment includesadministering to a patient in need of such treatment, a therapeuticallyeffective amount of a compound of the present invention, or apharmaceutically acceptable salt thereof.

Thus, in an exemplary embodiment, the present invention provides amethod of treating a disorder or condition through modulating a GR, themethod includes administering to a subject in need of such treatment, aneffective amount of a compound of the present invention, such as acompound of Formula (I).

The amount of GR modulator adequate to treat a disease throughmodulating the GR is defined as a “therapeutically effective dose.” Thedosage schedule and amounts effective for this use, i.e., the “dosingregimen,” will depend upon a variety of factors, including the stage ofthe disease or condition, the severity of the disease or condition, thegeneral state of the patient's health, the patient's physical status,age and the like. In calculating the dosage regimen for a patient, themode of administration also is taken into consideration.

The dosage regimen also takes into consideration pharmacokineticsparameters well known in the art, i.e., the rate of absorption,bioavailability, metabolism, clearance, and the like (see, e.g.,Hidalgo-Aragones (1996) J Steroid Biochem. Mol. Biol. 58:611-617;Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995)Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108;the latest Remington's, supra). The state of the art allows theclinician to determine the dosage regimen for each individual patient,GR modulator and disease or condition treated.

Single or multiple administrations of GR modulator formulations can beadministered depending on the dosage and frequency as required andtolerated by the patient. The formulations should provide a sufficientquantity of active agent to effectively treat the disease state. Thus,in one embodiment, the pharmaceutical formulations for oraladministration of GR modulator is in a daily amount of between about 0.5to about 20 mg per kilogram of body weight per day. In an alternativeembodiment, dosages are from about 1 mg to about 4 mg per kg of bodyweight per patient per day are used. Lower dosages can be used,particularly when the drug is administered to an anatomically secludedsite, such as the cerebral spinal fluid (CSF) space, in contrast toadministration orally, into the blood stream, into a body cavity or intoa lumen of an organ. Substantially higher dosages can be used in topicaladministration. Actual methods for preparing parenterally administrableGR modulator formulations will be known or apparent to those skilled inthe art and are described in more detail in such publications asRemington's, supra. See also Nieman, In “Receptor Mediated AntisteroidAction,” Agarwal, et al., eds., De Gruyter, New York (1987).

After a pharmaceutical composition including a GR modulator of theinvention has been formulated in an acceptable carrier, it can be placedin an appropriate container and labeled for treatment of an indicatedcondition. For administration of GR modulators, such labeling wouldinclude, e.g., instructions concerning the amount, frequency and methodof administration. In one embodiment, the invention provides for a kitfor the treatment of delirium in a human which includes a GR modulatorand instructional material teaching the indications, dosage and scheduleof administration of the GR modulator.

The terms and expressions which have been employed herein are used asteams of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding equivalents of thefeatures shown and described, or portions thereof, it being recognizedthat various modifications are possible within the scope of theinvention claimed. Moreover, any one or more features of any embodimentof the invention may be combined with any one or more other features ofany other embodiment of the invention, without departing from the scopeof the invention. For example, the features of the GR modulatorcompounds are equally applicable to the methods of treating diseasestates and/or the pharmaceutical compositions described herein. Allpublications, patents, and patent applications cited herein are herebyincorporated by reference in their entirety for all purposes.

EXAMPLES

The following examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

High Pressure Liquid Chromatography—Mass Spectrometry (LCMS) experimentsto determine retention times (RT) and associated mass ions wereperformed using one of the following methods. Solvent A is water andsolvent B is acetonitrile.

Method A: Experiments performed on a Micromass Platform LC spectrometerwith positive and negative ion electrospray and ELS/Diode arraydetection using a Phenomenex Luna C18(2) 30×4.6 mm column and a 2mL/minute flow rate. The solvent system was 95% solvent A and 5% solventB for the first 0.50 minutes followed by a gradient up to 5% solvent Aand 95% solvent B over the next 4 minutes. The final solvent system washeld constant for a further 0.50 minutes.

Method B: Experiments performed on a Micromass Platform LCT spectrometerwith positive ion electrospray and single wavelength UV 254 nm detectionusing a Higgins Clipeus C18 5 μm 100×3.0 mm column and a 2 mL/minuteflow rate. The initial solvent system was 95% water containing 0.1%formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid(solvent B) for the first minute followed by a gradient up to 5% solventA and 95% solvent B over the next 14 minutes. The final solvent systemwas held constant for a further 2 minutes.

Example 1 1,3-Dibenzyl-4-oxo-piperidine-3-carboxylic acid methyl ester(2: R^(1B)=H, Z=benzyl)

1-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloridesalt (1, Z=benzyl) (15 g, 52.9 mmol) was suspended in DMF (150 mL) andcooled to 0° C. Sodium hydride (4.23 g, 105.8 mmol) was addedportionwise over 1 h and the contents were allowed to warm to ambienttemperature and stir for a further 1 h. Benzyl bromide (6.3 mL, 53.0mmol) was added over 15 min and the contents were stirred for a further68 h at ambient temperature. 10 mL of water were added and the contentswere diluted with 400 mL of ethyl acetate, washed with water (200 mL),saturated sodium bicarbonate (200 mL) and brine (200 mL). The organiclayer was dried over magnesium sulfate, filtered and concentrated togive 20.5 g yellow oil that was purified by flash column chromatography(3:2 cyclohexane/CH₂Cl₂ to 100% CH₂Cl₂) to give 17.52 g (98%) of thetitle compound as a colorless oil. LC-MS: RT=2.80 min. (M+H)⁺ 338,(M-OMe)⁺ 306.

Example 2 1,3-Dibenzylpiperidin-4-one (3: R^(1B)=H, Z=benzyl)

1,3-Dibenzyl-4-oxo-piperidine-3-carboxylic acid methyl ester, (2,R^(1B)=H, Z=benzyl) (17.52 g, 51.92 mmol) was suspended in 150 mL of 6NHCl:MeOH (5:1) and the mixture was heated to reflux temperature withstirring for 48 h. After cooling the mixture was basified to pH 10 with6N NaOH and extracted with 3×200 mL dichloromethane. The combinedorganics were dried (MgSO₄) and concentrated to give 11.60 g of thetitle compound as a colorless oil, 80%. LC-MS: RT=0.38 min. (M+H)⁺ 280.

Example 3 2,8a-Dibenzyl-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one (4:R^(1B)=H, Z=benzyl)

1,3-Dibenzylpiperidin-4-one (3, R^(1B)=H, Z=benzyl) (3.98 g, 13.96 mmol)was added to a solution of sodium methoxide (0.83 g, 15.36 mmol) in 80mL of methanol and stirred at ambient temperature for 45 min. Thecontents were cooled to 0° C. and methylvinyl ketone (1.74 mL, 20.94mmol) was added over 30 min. The contents were allowed to warm toambient temperature and stir for 18 h. Concentrated HCl (1.55 mL) wasadded, the contents were stirred for a further 5 min and the solventswere evaporated to give a brown oil which was triturated in diethylether to give the title compound, 1.90 g. LC-MS: RT=2.26 min. (M+H)⁺332.

Example 4(R)-8a-Benzyl-6-oxo-3,4,6,7,8,8a-hexahydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (4: R^(1B)=H, Z=t-Butoxycarbonyl)

3-Benzyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1,Z=t-butoxycarbonyl) (11.50 g, 39.79 mmol) was dissolved in toluene (30mL) and (R)-(+)-α-methylbenzylamine (6.15 mL, 47.75 mmol) was added. Thecontents were heated to reflux for 20 h (with a Dean-Stark trap) andthen cooled to room temperature. The mixture was concentrated in vacuoand the resultant colorless oil (16.5 g, 39.79 mmol) was dissolved intoluene and cooled to 0° C. and methylvinyl ketone (4.0 mL, 47.45 mmol)was added dropwise. After 30 min the temperature was raised to 45° C.After 6 days at 45° C., acetic acid (20 mL) and water (20 mL) were addedand the contents were stirred at ambient temperature for 1 h. Theorganics were extracted with CH₂Cl₂ (50 mL), washed with water, driedwith MgSO₄, concentrated and purified by flash chromatography (CH₂Cl₂100% to 5% EtOAc in CH₂Cl₂) to afford 8.6 g of the intermediate diketone3-benzyl-5-(1-hydroxy-1-methyl-propyl)-3-methyl-4-oxo-piperidine-1-carboxylicacid tert-butyl ester as a colorless oil. The intermediate diketone (900mg, 2.50 mmol) was dissolved in methanol (14 mL) and sodium methoxide(20 mg, 1.30 mmol) was added and the contents were heated at 75° C. for3 h. The contents were cooled to 0° C. and acetic acid (135 μL) wasadded. The volatiles were removed and the residue was partitionedbetween EtOAc (10 mL) and saturated NaHCO₃ solution. The organic phasewas washed with brine and dried (MgSO₄). Purification by flashchromatography (CH₂Cl₂ 100% to 15% EtOAc in CH₂Cl₂) afforded 1.10 g ofthe title compound as a colorless oil. LC-MS (Method A): RT=3.84 mm,(M+H)⁺ no molecular ion seen.

Example 5 8a-Benzyl-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one (5A:R^(1B)=H)

Compound 4 (R^(1B)=H, Z=benzyl) (3.0 g (9.05 mmol) and α-chloroethylchloroformate (1.22 mL, 11.3 mmol) in dichloroethane (50 mL) were heatedto reflux under nitrogen for 18 h. After cooling, the mixture wasconcentrated in vacuo. Methanol (50 mL) was added and the contentsheated to reflux for 6 h. The solvents were removed by evaporation andthe residue was purified by flash column chromatography (100% CH₂Cl₂ toCH₂Cl₂/MeOH 9:1) to give the title compound as a pale brown solid, 1.51g. LC-MS: RT=1.67 min. (M+H)⁺ 242

The following compounds were prepared according to the proceduresdescribed in Examples 1 to 4:

8a-(3-Methoxybenzyl)-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one

8a-(4-Methoxybenzyl)-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one

8a-(4-Bromobenzyl)-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one

and

8a-(4-Nitrobenzyl)-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one

Example 62-Benzenesulfonyl-8a-benzyl-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one(10A: R^(1B)=H, R^(2A)=Ph)

Benzenesulfonyl chloride (90.0 mmol) was added to a stirred solution ofcompound 5 (R^(1B)=H) (25.0 mg, 90.0 mmol), triethylamine (25.0 μL, 180mmol) in 1,2-dichloroethane (3 mL). The resulting mixture was thenstirred at room temperature for 18 h. PS-Trisamine resin (33.0 mg,loading=4.11 mmol/g) was added and the mixture was agitated at roomtemperature for a further 24 h. The mixture was filtered and thefiltrate was purified by flash chromatography (CH₂Cl₂ 100% to 5% EtOAcin CH₂Cl₂) to afford the title compound 1 as a yellow oil, whichsolidified on standing. LC-MS: RT=3.68 min (M+H)⁺ 382.

Example 7(R)-8a-Benzyl-2-(4-tert-butyl-benzenesulfonyl)-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one(10A: R^(1B)=H, R^(2A)=(4-t-Butyl)phenyl)

To compound (R)-5A (R^(1B)=H, Z=t-butoxycarbonyl) (598 mg, 1.75 mmol)was added a 20% solution of TFA in CH₂Cl₂ and the contents were stirredat ambient temperature for 2.5 h. The solvents were then removed invacuo. The residue was dissolved in CH₂Cl₂ (5 mL) anddiisopropylethylamine (670 μL, 3.86 mmol) and 4-t-butylphenylsulfonylchloride (526 mg, 1.93 mmol) were added and the contents were stirredfor 18 h. Water (10 mL) was added and the organics were extracted withEtOAc (15 mL), washed with brine and dried (MgSO₄). Purification byflash chromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 600 mgof the title compound as an orange oil. LC-MS (Method A): RT=4.06 min,(M+H)⁺ 438.

Example 82,8aβ-Dibenzyl-1,3,4,4aα,5,7,8,8a-octahydro-2H-isoquinolin-6-one (6B:R^(1B)=H, R²=Phenyl)

Lithium metal (150 mg) was added to a flask charged with 75 mL of liquidammonia. 2,8a-Dibenzyl-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one (4,R^(1B)=H, Z=benzyl) (2.0 g) was added and the contents were stirred at−78° C. for 20 min. A further 150 mg of lithium metal was added andstirring continued for a further 15 min. Solid ammonium chloride wasadded until the blue color was discharged. The contents were warmed toambient temperature and extracted with dichloromethane. The organicphase was washed with saturated. ammonium chloride, dried andconcentrated to give a residue that was purified by flash columnchromatography (10% EtOAc in CH₂Cl₂) to give 0.60 g of the titlecompound. LC-MS: RT=2.15 min. (M+H)⁺ 334.

Example 9 8aβ-Benzyl-1,3,4,4aα,5,7,8,8a-octahydro-2H-isoquinolin-6-one(5B: R^(1B)=H)

Compound 6B (R^(1B)=H, R²=Ph) (1.14 g, 3.42 mmol) and palladiumhydroxide (0.35 g, 0.342 mmol) were suspended in 40 mL of acetic acidand hydrogenated at atmospheric pressure for 21 h. The reaction mixturewas filtered, concentrated and dissolved in CH₂Cl₂ and treated with 1MHCl in diethyl ether to give the title compound as its hydrochloridesalt, a beige solid, 0.96 g. LC-MS RT=1.67 min. (M+H)⁺ 244.

Example 102-Benzenesulfonyl-8aβ-benzyl-1,3,4,4a,α,5,7,8,8a-octahydro-2H-isoquinolin-6-one(10B: R^(1B)=H, R^(2A)=Phenyl)

8aβ-Benzyl-1,3,4,4aα,5,7,8,8a-octahydroisoquinolin-6-one (5B: R^(1B)=H)(84 mg, 0.348 mmol) and benzenesulfonyl chloride (49 μL, 0.383 mmol)were stirred in CH₂Cl₂ and diisopropylethylamine (73 μL) was added. Thecontents were stirred for 18 h, diluted with CH₂Cl₂, washed with water,brine, dried, concentrated and purified by flash column chromatography(10% EtOAc in CH₂Cl₂) to give the title compound as a waxy pale yellowsolid (83 mg). LC-MS: RT=3.24 min. (M+H)⁺ 384.

The following compound was similarly prepared:

8aβ-Benzyl-2-(4-tert-butylbenzenesulfonyl)-1,3,4,4aα,5,7,8,8a-octahydro-2H-isoquinolin-6-one

Example 112,8a-Dibenzyl-7-[1-hydroxy-meth-(Z)-ylidene]-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one(12A: R^(1B)=H, L²-R²=Benzyl)

Compound 6A (R^(1B)=H, L²-R²=benzyl) (0.31 g, 0.94 mmol) was dissolvedin toluene (2.5 mL). Ethyl formate (152 μL, 1.88 mmol) was addedfollowed by sodium methoxide (102 mg, 1.88 mmol). The contents wereheated to reflux for 90 min, then cooled, poured into water andextracted with CH₂Cl₂. The organic phase was washed with brine and dried(MgSO₄). Removal of solvent gave 334 mg of the title compound as anorange oil which was used in subsequent examples without furtherpurification. LC-MS (Method A): RT=2.33 min, (M+H)⁺ 360.

Example 128a-Benzyl-2-(4-tert-butylbenzenesulfonyl-7-hydroxymethylene-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one(12A: R^(1B)=H, L²-R²=SO₂(4-t-Butyl)phenyl)

Compound 10A (R^(1B)=H; R^(2A)=(4-t-butyl)phenyl) (100 mg, 0.229 mmol)was dissolved in toluene (1 mL). Ethyl formate (37 μL, 0.46 mmol) wasadded followed by sodium methoxide (25 mg, 0.46 mmol). The contents wereheated to reflux for 35 min, then cooled, poured into water andextracted with CH₂Cl₂. The organic phase was washed with brine and dried(MgSO₄). Removal of solvent gave 113 mg of the title compound as anorange glass which was used in subsequent examples without furtherpurification. LC-MS: RT=4.36 min. (M+H)⁺ 466, (M−H)⁻ 464.

Example 13(S)-8a-Benzyl-2-(4-tert-butyl-benzenesulfonyl)-7-[1-hydroxy-meth-(Z)-ylidene]-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one(12A: R^(1B)=H, L²-R²=SO₂(4-t-Butyl)phenyl)

Compound (R)-10A (R^(1B)=H, R^(2A)=(4-t-butyl)phenyl) (665 mg, 1.52mmol) was dissolved in methanol (5 mL) and sodium methoxide (234 mg,4.35 mmol) and ethyl formate (450 μL, 7.60 mmol) were added. After 1 h,water (5 mL) was added and the organics were extracted with EtOAc,washed with brine and dried (MgSO₄). Removal of solvent gave 532 mg ofthe title compound as an orange foam which was used in subsequentexamples without further purification. LC-MS (Method A): RT=4.40 min,(M+H)⁺ 466.

Example 148a-Benzyl-2-(4-tert-butylbenzenesulfonyl)-7-hydroxymethylene-octahydroisoquinolin-6-one.(12B: R^(1B)=H, L²-R²=SO₂(4-t-Butyl)phenyl)

Compound 10B (R^(1B)=H; R^(2A)=(4-t-butylphenyl)) (100 mg, 0.228 mmol)was dissolved in toluene (1 mL) and ethyl formate (25 mg, 0.46 mmol) wasadded followed by sodium methoxide (25 mg, 0.46 mmol). The contents wereheated to reflux for 35 min, then cooled, poured into water andextracted with CH₂Cl₂. The organics were washed with brine, dried(MgSO₄) and concentrated to give the title compound together with the5-hydroxymethylene regioisomer which were used directly in the followingExamples without further purification. LC-MS: RT=4.46 min. (M+H)⁺ 468.

Example 154a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene.(13A: R^(1B)=H, L²-R²=SO₂(4-t-Butyl)phenyl)

Compound 12A (R^(1B)=H, L²-R²=SO₂(4-t-butyl)Ph) (23 mg, 49.5 μmol) wassuspended in ethanol (1 mL) and hydrazine hydrate (10 μL, 0.32 mmol) wasadded and the contents were heated to reflux for 1.5 h. The volatileswere removed under vacuum to give 40 mg of an orange glass that waspurified by preparative HPLC to yield the title compound as a colorlessglass, 10 mg. LC-MS: RT=4.12 min. (M+H)⁺ 462.

The following compounds were similarly prepared:

4a-Benzyl-6-(4-morpholin-4-yl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.15 min, (M+H)⁺ 491.

4a-Benzyl-6-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.51 min, (M+H)⁺ 477.

Example 164a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-2-methyl-4,4a,5,6,7,8-hexahydro-2H-1,2,6-triazacyclopenta[b]naphthalene.(14A: R^(1B)=H, L²-R²=SO₂(4-t-Butyl)phenyl, R^(6C)=Me)

Compound 12A (R^(1B)=H, L²-R²=SO₂(4-t-butyl)phenyl) (20 mg, 43 μmol) wassuspended in ethanol (1 mL) and methyl hydrazine (15 μL, 0.28 mmol) wasadded. The contents were heated to 90° C. for 1.5 h, then cooled andevaporated to give 22 mg of an orange glass. Purification by preparativeHPLC yielded the title compound: 3.5 mg as a yellow glass. LC-MS:RT=4.39 min. (M+H)⁺ 476.

Example 174a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene.(15A: R^(1B)=H, L²-R²═SO₂(4-t-Butyl)phenyl)

Compound 12A (R^(1B)=H, L²-R²=SO₂(4-t-butyl)phenyl) (28 mg, 60.2 mmol),4-fluorophenylhydrazine hydrochloride (10.8 mg, 66.2 mmol) and sodiumacetate (5.4 mg, 66.2 μmol) were dissolved in acetic acid (0.8 mL) andheated to 90° C. for 18 h. The contents were cooled, poured into water,extracted with CH₂Cl₂, dried (MgSO₄) and concentrated to give 41 mg ofred-brown oil that was purified by preparative HPLC to give the titlecompound as an orange-brown glass, 8 mg. LC-MS: RT=4.85 min. (M+H)⁺ 556.

The following compounds were similarly prepared:

(S)-4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

(S)-4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-1-(4-methoxy-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.78 min, (M+H)⁺ 568.

(S)-4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-1-p-tolyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.96 min, (M+H)⁺ 552.

1,4a-Dibenzyl-6-(4-tert-butyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.73 min, (M+H)⁺ 552.

4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-1-(4-trifluoromethyl-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=5.03 min, (M+H)⁺ 606.

4-[4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-1-yl]-benzonitrile

LC-MS (Method A): RT=4.74 min, (M+H)⁺ 563.

4-[4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-1-yl]-benzenesulfonamide

LC-MS (Method A): RT=4.25 min, (M+H)⁺ 617.

3-[4a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-1-ylmethyl]-phenol

LC-MS (Method A): RT=4.33 min, (M+H)⁺ 568.

Example 184a,6-Dibenzyl-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene(15A: R^(1B)=H, L²-R²=benzyl)

Compound 12A (R^(1B)=H, L²-R²=benzyl) (167 mg, 0.47 mmol) and4-fluorophenylhydrazine hydrochloride (163 mg, 2.79 mmol) were dissolvedin acetic acid (2.5 mL) and heated to 90° C. for 2 hours. The contentswere cooled, poured into water, extracted with CH₂Cl₂, dried (MgSO₄) andconcentrated. Purification by flash chromatography (CH₂Cl₂ 100% to 15%EtOAc in CH₂Cl₂) afforded 41 mg of the title compound as an orange oil.LC-MS (Method A): RT=2.75 min, (M+H)⁺ 450.

The following compounds were similarly prepared:

6-Benzyl-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.80 min, (M+H)⁺ 468.

6-Benzyl-1-(4-fluoro-phenyl)-4a-(4-methoxy-benzyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.69 min, (M+H)⁺ 480.

Example 194a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1-oxa-2,6-diazacyclopenta[b]naphthalene.(16A: R^(1B)=H, L²-R²=SO₂(4-t-Butyl)phenyl)

Compound 12A (R^(1B)=H, L²-R²=SO₂(4-t-butyl)phenyl) (21 mg, 45 μmol) andhydroxylamine sulfate (4 mg, 22.5 μmol) were dissolved in ethyl acetate(1 mL), acetic acid (0.2 mL) and water (0.1 mL) and heated to 90° C. for19 h. The contents were evaporated to dryness and purified bypreparative HPLC to yield the title compound, 0.9 mg. LC-MS: RT=4.49min. (M+H)⁺ 463.

Example 2010a-Benzyl-6-(4-tert-butyl-benzenesulfonyl)-2-methyl-5,6,7,8,10,10a-hexahydro-1,3,6-triaza-anthracene(17A: R^(5D)=Methyl; R^(1B)=H; L²-R²=SO₂(4-t-butylphenyl)

Compound 12A (R^(1B)=H; L²-R²=SO₂(4-t-butylphenyl) (50 mg, 0.11 mmol)was heated with acetamidine hydrochloride (61 mg, 0.65 mmol) in DMF (0.5mL) at 180° C. using microwave irradiation for 10 min. Water (5 mL) wasadded and the organics were extracted with CH₂Cl₂ (3×5 mL) and washedwith brine and dried (MgSO₄). Purification by preparative HPLC afforded6 mg of the title compound as a yellow oil. LC-MS (Method A): RT=4.01min, (M+H)⁺ 488.

Example 214a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-2H-1,2,6-triazacyclopenta[b]naphthalene.(13B: R^(1B)=H, L²-R²=SO₂(4-t-Butyl)phenyl)

The mixture of compound 12B (R^(1B)=H, L²-R²=SO₂(4-t-butyl)phenyl) andits regioisomer (29 mg, 42.8 μmol), hydrazine hydrate (9 μL, 0.278 mmol)and ethanol (1 mL) were heated at 90° C. for 1.5 h. The volatiles wereremoved under vacuum to give 21 mg of a glass that was purified bypreparative HPLC to give the title compound as an off-white solid, 16mg. LC-MS: RT=4.03 min. ((M+H)⁺ 464.

Example 224a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triazacyclopenta[b]naphthalene.(15B: R^(1B)=H, L²-R²=SO₂(4-t-Butyl)phenyl)

The mixture of compound 12B (R^(1B)=H, L²-R²=SO₂(4-t-butyl)phenyl) andits regioisomer (20 mg, 42.8 μmol) and 4-fluorophenylhydrazinehydrochloride (7.6 mg, 47.1 μmol)) were dissolved in acetic acid andsodium acetate (4 mg, 47.1 mmol) added. The contents were heated to 90°C. for 16 h, then cooled and poured into water and extracted withCH₂Cl₂. The organics were washed with brine, dried (MgSO₄) andconcentrated to give 22 mg crude product which was purified bypreparative HPLC to yield the title compound as a brown glass, 11 mg.LC-MS: RT=4.93 mins. (M+H)⁺ 558.

Example 234a-Benzyl-6-(4-tert-butylbenzenesulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1-oxa-2,6-diazacyclopenta[b]naphthalene.(16B: R^(1B)=H, L²-R²=SO₂(4-t-Butyl)phenyl)

The mixture of compound 12B (R^(1B)=H, L²-R²=SO₂(4-t-butyl)phenyl) andits regioisomer (20 mg, 42.8 μmol) were dissolved in ethanol (0.6 mL)and acetic acid (0.2 mL) and water (0.1 mL) were added, followed byhydroxylamine hydrochloride (3.8 mg, 54.6 μmol). The contents wereheated to 90° C. for 19 h, the volatiles were removed and the residuewas purified by preparative HPLC to yield the title compound as anoff-white solid, 7 mg. LC-MS: RT=4.47 min. (M+H)+ 465

Example 24(R)-7-Acetoxy-2-(4-tert-butyl-benzenesulfonyl)-6-oxo-2,3,4,6,7,8-hexahydro-1H-isoquinoline-8a-carboxylicacid methyl ester (24A: L¹-R¹=CO₂Me; L²-R²=SO₂(4-t-Butyl)phenyl)

To a solution of compound (R)-23A (L¹-R¹=CO₂Me;L²-R²=SO₂(4-t-butyl)phenyl)) (1.00 g, 2.47 mmol) in toluene (50 mL) wasadded manganese acetate dihydrate (3.69 g, 13.79 mmol). The contentswere heated for 18 h at reflux under a Dean-Stark trap. The solventswere removed and the residue was purified by flash chromatography(CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) to afford 775 mg of the titlecompound as an off white solid. LC-MS (Method A): RT=3.82 min, (M+H)⁺464.

Example 25(R)-6-(4-tert-Butyl-benzenesulfonyl)-2-methyl-1,4,5,6,7,8-hexahydro-1,3,6-triaza-cyclopenta[b]naphthalene-4a-carboxylicacid methyl ester (25A: L¹-R¹=CO₂Me; L²-R²=SO₂(4-t-Butyl)phenyl)

To a solution of compound 24A (L¹-R¹=CO₂Me; L²-R²=SO₂(4-t-butyl)phenyl))(600 mg, 1.29 mmol) in ethanol (4 mL) was added copper^(II) acetate (470mg, 2.59 mmol), aqueous ammonia (3 mL) and acetaldehyde (5 mL) and thecontents were heated for 5 h at reflux. The solvents were removed,NaHCO₃ (20 mL) was added, and the organics were extracted with CH₂Cl₂(20 mL), washed with brine and dried (MgSO₄). Purification by flashchromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 432 mg ofthe title compound as an off white solid. LC-MS (Method A): RT=2.53 min,(M+H)⁺ 444.

Example 26(S)-8a-Methyl-6-oxo-3,4,6,7,8,8a-hexahydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (36A: L²-R²=CO₂-t-Butyl)

1-Benzyl-3-methyl-piperidin-4-one (15.0 g, 73.89 mmol) was dissolved intoluene (150 mL) and (R)-(+)-α-methylbenzylamine (11.4 mL, 88.67 mmol)was added. The contents were heated to reflux for 20 h (Dean-Stark trap)and then cooled to room temperature. The resultant colorless oil wasdissolved in THF and methylvinylketone (7.40 mL, 88.67 mmol) andhydroquinone (150 mg, catalytic) were added and the contents werestirred in the dark. After 2 days 1N HCl (90 mL) was added and thecontents stirred at ambient temperature for 30 min, the organics wereextracted with diethyl ether (100 mL), washed with water, dried withMgSO₄, concentrated and purified by flash chromatography (CH₂Cl₂ 100% to20% EtOAc in CH₂Cl₂) to afford 6.51 g of((R)-1-benzyl-3-methyl-3-(3-oxo-butyl)-piperidin-4-one as a colorlessoil. LC-MS (Method A): RT=0.32 min, (M+H)⁺ 274.

This material (6.5 g, 23.80 mmol) was dissolved in ethanol (100 mL) and20% palladium hydroxide on carbon (500 mg) and di-tort-butyl dicarbonate(7.8 g, 35.71 mmol) were added. The contents were stirred under ahydrogen atmosphere for 18 h. The catalyst was removed by filtration andfiltrate evaporated to dryness. Purification by flash chromatography(20% tert-butyl methylether in cyclohexanone) afforded 6.16 g of(R)-3-methyl-4-oxo-3-(3-oxo-butyl)-piperidine-1-carboxylic acidtert-butyl ester as a colorless oil. LC-MS (Method A): RT=3.03 min,(M+H)⁺=284. To a solution of this material (6.10 g, 21.55 mmol) inmethanol (100 mL) was added sodium methoxide (3.84 g, 43.10 mmol) andthe contents heated at 50° C. for 18 hours. The volatiles were removedand the residue partitioned between EtOAc (50 mL) and water then theorganic phase washed with brine and dried (MgSO₄). Purification by flashchromatography (CH₂Cl₂ 100% to 10% EtOAc in CH₂Cl₂) afforded 3.33 g ofthe title compound as a colorless oil. LC-MS (Method A): RT=3.15 min,(M+H)⁺ 266.

Example 27(S)-7-[1-Hydroxy-meth-(Z)-ylidene]-8a-methyl-6-oxo-3,4,6,7,8,8a-hexahydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (37A: R⁵=4-F-Phenyl, L²-R²=CO₂-t-Butyl)

To a solution of diisopropylamine (3.05 mL, 21.79 mmol) in diethyl ether(50 mL) at −78° C. was added n-butyl lithium (12.45 mL, 1.6 M solution,19.92 mmol). Compound (S)-36A (L²-R²=CO₂-t-butyl) (665 mg, 1.52 mmol) indiethyl ether (10 mL) was then added followed by the addition oftrifluorethyl orthoformate (6.00 g, 46.81 mmol) after 20 min. After afurther 90 min, 2N HCl (30 mL) was added and the contents were warmed toambient temperature. Water (15 mL) and EtOAc (50 mL) were added and theorganic phase was separated, washed with brine and dried (MgSO₄).Removal of solvent gave 1.45 g of the title compound as a yellow powderthat was used in subsequent examples without further purification. LC-MS(Method A): RT=3.56 min, (M+H)⁺ no molecular ion seen.

Example 28(S)-1-(4-Fluoro-phenyl)-4a-methyl-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-carboxylicacid tert-butyl ester (40A: R⁵=4-F-Phenyl, L²-R²=CO₇-t-Butyl)

Compound 37A (L²-R²=CO₂-t-butyl) (2.50 g, 8.53 mmol) was suspended inacetic acid (25 mL) and sodium acetate (1.05 g, 12.80 mmol) and4-fluorophenylhydrazine hydrochloride (2.08 g, 12.80 mmol) were added.After 2 h water (40 mL) was added and the organics were extracted withEtOAc (40 mL), washed with brine and dried (MgSO₄). Purification byflash chromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) to afford 2.21g of the title compound as a cream colored solid. LC-MS (Method A):RT=3.52, (M+H)⁺=384.

Example 29(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene(40A: L2-R2=SO2(4-t-Butyl)phenyl)

To compound 37A (L²-R²=CO₂-t-butyl) (290 mg, 0.78 mmol) was added a 20%solution of TFA in CH₂Cl₂ (3 mL) and the contents were stirred atambient temperature for 2.5 h. The solvents were then removed. Theresidue was dissolved in CH₂Cl₂ (2 mL) and diisopropylethyl amine (540μL, 3.88 mmol) and 4-tert-butylphenylsulfonyl chloride (199 mg, 0.85mmol) were added and the contents were stirred for 18 h. Water (10 mL)was added and the organics were extracted with EtOAc (15 mL), washedwith brine and dried (MgSO₄). Purification by flash chromatography(CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 600 mg of the titlecompound as white solid. LC-MS (Method A): RT=4.57 min, (M+H)⁺ 480.

The following compounds were similarly prepared:

(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.93 min, (M+H)⁺ 424.

(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.11 min, (M+H)⁺ 438.

(S)-1-(4-Trifluoromethyl-phenyl)-4a-methyl-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): (M+H)⁺ 492.

(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-(4-morpholin-4-yl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.81 min, (M+H)⁺ 509.

(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.01 min, (M+H)⁺ 495.

4-[(S)-1-(4-Fluoro-phenyl)-4a-methyl-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-sulfonyl]-benzonitrile

LC-MS (Method A): RT=3.85 min, (M+H)⁺ 449.

(S)-1-(4-Fluoro-phenyl)-6-(4-methoxy-benzenesulfonyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.86 min, (M+H)⁺ 454.

(S)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.90 min, (M+H)⁺ 442.

(S)-6-(2-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.87 min, (M+H)⁺ 442

(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-(toluene-2-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.02 min, (M+H)⁺ 438.

(S)-6-Benzyl-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.34 min, (M+H)⁺ 374.

(S)-1-(4-Fluoro-phenyl)-4a-methyl-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-sulfonicacid phenylamide

LC-MS (Method A): RT=3.82 min, (M+H)⁺ 439.

(S)-6-(4,4-Dimethyl-piperidine-1-sulfonyl)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.38 min, (M+H)⁺ 459.

(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-(piperidine-1-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.85 min, (M+H)⁺ 431.

(S)-6-(4-tert-Butyl-benzenesulfonyl)-4a-methyl-1-pyridin-4-yl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.11 min, (M+H)⁺ 463.

(S)-6-(4-tert-Butyl-benzenesulfonyl)-4a-methyl-1-pyridin-2-yl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.10 min, (M+H)⁺ 463.

4-[(S)-1-(4-Fluoro-phenyl)-4a-methyl-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-sulfonyl]-phenylamine

LC-MS (Method A): RT=3.53 min, (M+H)⁺ 439.

(S)-1-(4-Fluoro-phenyl)-4a-methyl-6-trimethylacetyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): (M+H)⁺ 368.

Example 30 (S)-4-Oxo-3-(3-oxo-butyl)-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (46: L²-R²=CO₂-t-Butyl)

(S)-4-Oxo-3-(3-oxo-butyl)-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (35.0 g, 0.14 mol) was dissolved in toluene (150mL) and (S)-2-amino-N,N-diethyl-3-methyl-butyramide (27.7 g, 0.16 mol)and concentrated HCl (2 mL) were added. The contents were heated toreflux for 3 h over 4 Å molecular sieves. The resultant colorless oilwas dissolved in acetone (300 mL) and copper^(II) acetate (2.19 g,catalytic) were added and the mixture was heated at reflux for 20 min.Methylvinylketone (27.3 mL, 0.48 mmol) mmol) was added via the condenserand the contents were heated at reflux. After 2 h the mixture was cooledto ambient temperature and 2N HCl (200 mL) was added and the contentswere stirred at ambient temperature for 10 min. The organics wereextracted with EtOAc (100 mL), washed with water, dried with MgSO₄,concentrated and purified by flash chromatography (CH₂Cl₂ 100% to 5%acetone in CH₂Cl₂) to afford 30.58 g of the title compound as anoff-white solid. LC-MS (Method A): RT=3.86 min, (M+H)⁺ 314.

Example 31(R)-6-Oxo-4,6,7,8-tetrahydro-3H-isoquinoline-2,8a-dicarboxylic acid2-tert-butyl ester 8a-methyl ester (47A: L²-R²=CO₂-t-Butyl)

Compound 46 (L²-R²=CO₂-t-butyl) (30.0 g, 91.74 mmol) was dissolved inCH₂Cl₂ (300 mL) and pyrrolidine (6.5 mL, 77.98 mmol) and acetic acid(4.5 mL, 77.98 mmol) were added. The contents were stirred for 18 h atambient temperature. The solvent was removed and the residue wasdissolved in EtOAc, washed with water, 2M HCl, and brine, dried (MgSO₄)and concentrated in vacuo. Trituration with 50% diethyl ether incyclohexane afforded 19.48 g of the title compound as a cream coloredsolid. LC-MS (Method A): RT=3.26 min, (M+H)⁺=310.

Example 32(R)-7-[1-Hydroxymeth-(Z)-ylidene]-6-oxo-4,6,7,8-tetrahydro-3H-isoquinoline-2,8a-dicarboxylicacid 2-tert-butyl ester 8a-methyl ester (48A: L²-R²=CO₇-t-Butyl)

To a solution of diisopropylamine (0.79 mL, 5.66 mmol) in diethyl ether(20 mL) at −78° C. was added n-butyl lithium (3.20 mL, 1.6 M solution,5.17 mmol). Compound 47A (L²-R²=CO₂-t-butyl) (1.0 g, 3.23 mmol) indiethyl ether (5 mL) was added followed by the addition of trifluorethylorthoformate (1.20 mL, 12.92 mmol) after 20 min. After a further 90 min,2N HCl (10 mL) was added and the contents were allowed to warm toambient temperature. Water (10 mL) and EtOAc (20 mL) were added and theorganic phase was separated, washed with brine and dried (MgSO₄).Removal of solvent gave 0.77 g of the title compound as a yellow powder,which was used in subsequent examples without further purification.LC-MS (Method A): RT=3.65 min, (M+H)⁺ 338.

Example 33(R)-1-(4-Fluoro-phenyl)-1,4,7,8-tetrahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a,6-dicarboxylicacid 6-tert-butyl ester 4a-methyl ester (49A: R⁵=4-F-Ph;L²-R²=CO₂-t-Butyl)

Compound 48A (L²-R²=CO₂-t-butyl) (7.90 g, 23.44 mmol) was suspended inacetic acid (75 mL) and sodium acetate (2.90 g, 35.16 mmol) and4-fluorophenylhydrazine hydrochloride (5.70 g, 35.16 mmol) were added.After 1 h water (60 mL) was added and the organics were extracted withEtOAc (60 mL) and washed with brine and dried (MgSO₄). Purification byflash chromatography (CH₂Cl₂ 100% to 5% acetone in CH₂Cl₂) to afford3.05 g of the title compound as a cream colored solid. LC-MS (Method A):RT=3.72 min, (M+H)⁺=428.

Example 34(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylicacid methyl ester (49A: R⁵=4-F-Ph; L²-R²=SO₂(4-t-Butyl)phenyl)

To compound 48A (R⁵=4-F-Ph; L²-R²=CO₂-t-Butyl) (2.0 g, 4.68 mmol) wasadded a 20% solution of TFA in CH₂Cl₂ (15 mL) and the contents werestirred at ambient temperature for 1. The solvents were then removed invacuo. The residue was dissolved in CH₂Cl₂ (2 mL) and diisopropylethylamine (3.38 mL, 7.03 mmol) and 4-t-butylphenylsulfonyl chloride (2.26mg, 7.03 mmol) were added and the contents were stirred for 2 h. Water(50 mL) was added and the organics were extracted with EtOAc (50 mL) andwashed with brine and dried (MgSO₄). Purification by flashchromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 2.05 g ofthe title compound as white solid. LC-MS (Method A): RT=4.34 min, (M+H)⁺524.

The following compounds were similarly prepared:

(R)-1-Butyl-6-(4-tert-butyl-benzenesulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylicacid methyl ester

LC-MS (Method A): RT=4.24 min, (M+H)⁺ 486.

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-isopropyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylicacid methyl ester

LC-MS (Method A): RT=3.88 min, (M+H)⁺ 472.

Example 35[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-methanol(50A: R⁵=4-F-Ph; L²-R²=SO₂(4-t-Butyl)phenyl)

To compound 49A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butyl)phenyl) (100 mg, 0.19mmol) in CH₂Cl₂ (2 mL) was added DIBAL-H (420 μL, 1.0 M solution, 0.42mmol) at −78° C. and the contents were stirred for 1 h. The reaction wasquenched by the addition of water (1 mL). The organics were extractedwith CH₂Cl₂ (10 mL), washed with brine and dried (MgSO₄). Purificationby flash chromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 31mg of the title compound as white solid. LC-MS (Method A): RT=4.16 min,(M+H)⁺ 496.

The following compounds were similarly prepared:

[(R)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-methanol

LC-MS (Method A): RT=3.57 min, (M+H)⁺ 458.

[(R)-1-(4-Fluoro-phenyl)-6-(toluene-4-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-methanol

LC-MS (Method A): RT=3.68 min, (M+H)⁺ 454.

[(R)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-methanol:

LC-MS (Method B): RT=10.89 min, (M+H)⁺ 440.

Example 36(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene(51A: R⁵=4-F-Ph; R^(1A)=Me; L²-R²=SO₂(4-t-Butylphenyl)

To compound 49A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (100 mg, 0.20mmol) in THF (1 mL) was added sodium hydride (24 mg, 0.60 mmol) andiodomethane (37 μL, 0.60 mmol) and the mixture was stirred at 75° C. for18 h. The cooled contents were partitioned between EtOAc (10 mL) andwater (10 mL) and washed with brine and dried (MgSO₄). Purification byflash chromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 38 mgof the title compound as white solid. LC-MS (Method A): RT=4.51 min,(M+H)⁺ 510.

The following compounds were similarly prepared:

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A) RT=4.68 min, (M+H)⁺ 534.

(R)-6-(Benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-hydroxy-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A) (M+H)⁺ 484.

(R)-6-(4-tert-Butyl-benzenesulfonyl)-4a-ethoxymethyl-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.57 min, (M+H)⁺ 524.

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(3-methoxy-propoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.69 min, (M+H)⁺ 568.

3-[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethoxy]-propionitrile

LC-MS (Method A): RT=4.38 min, (M+H)⁺ 549.

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-morpholin-4-yl-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.90 min, (M+H)⁺ 609.

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-piperidin-1-yl-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.94 min, (M+H)⁺ 607.

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-pyrrolidin-1-yl-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.92 min, (M+H)⁺ 593.

(R)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B): RT=12.26 min, (M+H)⁺ 516.

(R)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B): RT=12.47 min, (M+H)⁺ 472.

(R)-1-(4-Fluoro-phenyl)-4a-methoxymethyl-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B):: RT=12.81 min, (M+H)⁺ 468.

(R)-1-(4-Fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B):: RT=12.67 min, (M+H)⁺ 512.

(R)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.88 min, (M+H)⁺ 498.

(R)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.93 min, (M+H)⁺ 454.

(R)-1-(4-Fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-sulfonicacid dimethylamide

LC-MS (Method A): RT=3.58 min, (M+H)⁺ 465.

(R)-1-(4-Fluoro-phenyl)-4a-methoxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-sulfonicacid dimethylamide

LC-MS (Method A): RT=3.62 min, (M+H)⁺ 421.

(R)-6-(Butane-1-sulfonyl)-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.05 min, (M+H)⁺ 478.

(R)-(4-tert-butyl-benzenesulfonyl)-4a-(2-methoxy-ethoxymethyl)-1-methyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.87 min, (M+H)⁺ 474.

(R)-1-Butyl-6-(4-tert-butyl-benzenesulfonyl)-4a-(2-methoxy-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.36 min, (M+H)⁺ 516.

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-isopropyl-4a-(2-methoxy-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.03 min, (M+H)⁺ 502.

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-isopropyl-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.07 min, (M+H)⁺ 458.

(R)-1-Butyl-4a-methoxymethyl-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.78 min, (M+H)⁺ 430.

(R)-1-Butyl-4a-(2-methoxy-ethoxymethyl)-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.74 min, (M+H)⁺ 474.

Example 37(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbaldehyde(52A: R³=4-F-Ph; L²-R²=SO₂(4-t-Butylphenyl)

Oxalyl chloride (0.23 mL, 2.57 mmol) in CH₂Cl₂ (10 mL) was cooled to−78° C. and DMSO (0.4 mL, 5.62 mmol) in CH₂Cl₂ (4 mL) was added. After 5min, compound 49A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (0.58 g, 1.17mmol) was added and the contents were stirred for 20 min. Triethylamine(0.81 mL, 5.85 mmol) was added and the contents were warmed to ambienttemperature. The organics were partitioned between EtOAc (10 mL) andwater (10 mL), washed with brine and dried (MgSO₄). Purification byflash chromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 42 mgof the title compound as white solid. LC-MS (Method A): RT=4.13 min,(M+H)⁺ 494.

Example 38[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine(53A: R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl), R^(1C)=R^(1D)=Methyl)

To a solution of compound 52A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (50mg, 0.10 mmol) in dichloroethane (1 mL) was added dimethylamine (0.1 mL,0.20 mmol) and sodium triacetoxyborohydride (30 mg, 0.14 mmol). Thecontents were stirred for 18 h at ambient temperature, NaHCO₃ (2 mL) wasadded, and the organics were extracted with CH₂Cl₂ (10 mL), washed withbrine and dried (MgSO₄). Purification by flash chromatography(Amino-SPE: CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 61 mg of thetitle compound as an off white solid. LC-MS (Method A): RT=2.79 min,(M+H)⁺ 523.

The following compounds were similarly prepared:

(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-4-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.73 min, (M+H)⁺ 565.

(S)-6-(4-Trifluoromethyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-4-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): (M+H)⁺ 577.

(S)-6-(1-Cyclopropylmethylsulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-4-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (M+H)⁺ 485.

(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-pyrrolidin-1-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.91 min, (M+H)⁺ 549.

([(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-ethyl-amine

LC-MS (Method A): RT=2.82 min, (M+H)⁺ 523.

[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-diethyl-amine

LC-MS (Method A): RT=2.92 min, (M+H)⁺ 551.

(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-piperidin-1-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.99 min, (M+H)⁺ 563.

[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-(2-methoxy-ethyl)-amine

LC-MS (Method A): RT=2.74 min, (M+H)⁺ 553.

(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(4-methyl-piperazin-1-ylmethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.83 min, (M+H)⁺ 578.

N′-[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-N,N-dimethyl-ethane-1,2-diamine

LC-MS (Method A): RT=2.63 min, (M+H)⁺ 566.

N-[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-N,N,N-trimethyl-ethane-1,2-diamine

LC-MS (Method A): RT=2.96 min, (M+H)⁺ 580.

N′-[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-N,N-dimethyl-propane-1,3-diamine

LC-MS (Method A): RT=2.20 min, (M+H)⁺ 580.

N-[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-N,N′,N′-trimethyl-propane-1,3-diamine

LC-MS (Method A): RT=2.29 min, (M+H)⁺ 594.

[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-(2-methoxy-ethyl)-methyl-amine

LC-MS (Method A): RT=2.91 min, (M+H)⁺ 567.

[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-isopropyl-amine

LC-MS (Method A): RT=2.88 min, (M+H)⁺ 537.

(S)-4a-Azetidin-1-ylmethyl-6-(4-tert-butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.85 min, (M+H)⁺ 535.

Allyl-[(S)-6-(4-tert-butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-amine

LC-MS (Method A): RT=2.71 min, (M+H)⁺ 535.

2-{[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7-8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-amino}-ethanol

LC-MS (Method A): RT=2.74 min, (M+H)⁺ 539.

[(S)-1-(4-Fluoro-phenyl)-6-(toluene-4-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine

LC-MS (Method A): RT=2.50 min, (M+H)⁺ 481.

(S)-1-(4-Fluoro-phenyl)-4a-pyrrolidin-1-ylmethyl-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.55 min, (M+H)⁺ 507.

[(S)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine

LC-MS (Method A): RT=2.45 min, (M+H)⁺ 485.

(S)-6-(4-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-pyrrolidin-1-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.51 min, (M+H)⁺ 511.

(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-pyrrolidin-1-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.49 min, (M+H)⁺ 492.

(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine

LC-MS (Method A): RT=2.41 min, (M+H)⁺ 467.

(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-morpholin-4-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B): RT=9.11 min, (M+H)⁺ 509.

2-{[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-methyl-amino}-ethanol

LC-MS (Method B): RT=8.90 min, (M+H)⁺ 553.

(S)-6-(Butane-1-sulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-4-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.74 min, (M+H)⁺ 489.

4-[(S)-1-(4-Fluoro-phenyl)-4a-morpholin-4-ylmethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-sulfonyl]-benzonitrile

LC-MS (Method A): RT=2.97 min, (M+H)⁺ 534.

[(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-diethyl-amine

LC-MS (Method A): RT=2.50 min, (M+H)⁺ 495.

Diethyl-[(S)-1-(4-fluoro-phenyl)-6-(4-methoxy-benzenesulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-amine

LC-MS (Method A): RT=2.56 min, (M+H)⁺ 525.

(S)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-piperidin-1-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.52 min, (M+H)⁺ 507.

(S)-1-(4-Fluoro-phenyl)-6-(4-methoxy-benzenesulfonyl)-4a-piperidin-1-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.57 min, (M+H)⁺ 537.

(S)-1-Butyl-4a-piperidin-1-ylmethyl-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.54 min, (M+H)⁺ 483.

(S)-6-(4-tert-Butyl-benzenesulfonyl)-4a-pyrrolidin-1-ylmethyl-1-(2,2,2-trifluoro-ethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.74 min, (M+H)⁺ 537.

[(S)-1-Butyl-6-(4-tert-butyl-benzenesulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine

LC-MS (Method A): RT=2.76 min, (M+H)⁺ 485.

(S)-1-Butyl-6-(4-tert-butyl-benzenesulfonyl)-4a-piperidin-1-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.85 min, (M+H)⁺ 525.

[(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-isopropyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-ylmethyl]-dimethyl-amine

LC-MS (Method A): RT=2.47 min, (M+H)⁺ 471.

(S)-6-(4-tert-Butyl-benzenesulfonyl)-1-isopropyl-4a-piperidin-1-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.58 min, (M+H)⁺ 511.

(S)-1-(4-Fluoro-phenyl)-4a-morpholin-4-ylmethyl-6-(toluene-2-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B): RT=9.18 min, (M+H)⁺ 523.

(S)-6-(2-Fluoro-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-4-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B): RT=8.67 min, (M+H)⁺ 527.

(S)-1-(4-Fluoro-phenyl)-4a-morpholin-4-ylmethyl-6-(pyridine-2-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B): RT=7.27 min, (M+H)⁺ 510.

Example 39(4aR,8aS)-1-(4-Fluoro-phenyl)-1,4,7,8,8a,9-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a,6-dicarboxylicacid 6-tert-butyl ester 4a-methyl ester (49B: R⁵=4-F-Ph;L²-R²=CO₂-t-Butyl)

A solution of compound 49A (R⁵=4-F-Ph; L²-R²=CO₂-t-butyl) (400 mg, 0.94mmol) in methanol (10 mL) was treated with platinum oxide (32 mg, 0.14mmol) and stirred under a hydrogen atmosphere for 2 h. The solution wasfiltered and the filtrate was evaporated to dryness to afford 412 mg ofthe title compound as a colorless oil which was used in subsequentexamples without further purification. LC-MS (Method A): RT=3.74 min,(M+H)⁺ 430.

Example 40(4aR,8aS)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8,8a,9-octahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylicacid methyl ester (49B: R⁵=4-F-Ph; L²-R²=SO₂(4-t-Butylphenyl)

To compound 49B (R⁵=4-F-Ph; L²-R²=CO₂-t-butyl) (404 mg, 0.94 mmol) wasadded a 20% solution of TFA in CH₂Cl₂ (4 mL) and the contents werestirred at ambient temperature for 1 h. The solvents were then removed.The residue was dissolved in CH₂Cl₂ (4 mL) and diisopropylethyl amine(485 μL, 2.79 mmol) and 4-tert-butylphenylsulfonyl chloride (540 mg,2.32 mmol) were added and the contents were stirred for 3 h. Water (10mL) was added and the organics were extracted with EtOAc (15 mL), washedwith brine and dried (MgSO₄). Purification by flash chromatography(CH₂Cl₂ 100% to 40% EtOAc in CH₂Cl₂) to afforded 352 mg of the titlecompound as a yellow foam. LC-MS (Method A): RT=4.36 min, (M+H)⁺ 526.

Example 41[(4aR,8aS)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8,8a,9-octahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-methanol(50B: R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl)

To compound 49B (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (500 mg, 0.95mmol) in CH₂Cl₂(10 mL) was added DIBAL-H (3.8 mL, 1.0 M solution, 3.80mmol) at −78° C. and the contents were stirred for 1 h. The reaction wasquenched by the addition of water (10 mL). The organics were extractedwith CH₂Cl₂ (50 mL) and washed with brine and dried (MgSO₄).Purification by flash chromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂)afforded 286 mg of the title compound as white solid. LC-MS (Method A):RT=4.14 min, (M+H)⁺ 496.

Example 42(4aR,8aS)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-methoxymethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene(51B: R^(1A)=Me; R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl)

To compound SOB (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (40 mg, 0.08mmol) in THF (1 mL) was added a sodium hydride (10 mg, 0.24 mmol) andiodomethane (15 μL, 0.24 mmol) and the contents were stirred at 70° C.for 18 h. The cooled contents were partitioned between EtOAc (10 mL) andwater (10 mL) and washed with brine and dried (MgSO₄). Purification byflash chromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 21 mgof the title compound as white solid. LC-MS (Method B): RT=14.12 min,(M+H)⁺ 512.

The following compounds were similarly prepared:

(4aR,8aS)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B): RT=14.04 min, (M+H)⁺ 556.

(4aR,8aS)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethoxymethyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B): RT=11.92 min, (M+H)⁺ 500.

(4aR,8aS)-6-Benzenesulfonyl-1-(4-fluoro-phenyl)-4a-methoxymethyl4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method B): RT=12.06 min, (M+H)⁺ 456.

Example 43(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylicacid (54A: R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl)

A solution of compound 49A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (545mg, 1.04 mmol) in methanol (10 mL) was treated with 1M LiOH (3.1 mL,3.12 mmol) and the contents were stirred at ambient temperature for 18h. The solvents were removed and the residue was dissolved in CH₂Cl₂,washed with 1 M citric acid and dried (MgSO₄). Removal of solvent gave504 mg of the title compound as a yellow solid, which was used insubsequent examples without further purification. LC-MS (Method A):RT=4.06 min, (M+H)⁺ 510.

Example 44(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylicacid benzylamide (55A: R^(1C)=R^(1D)=Benzyl; R⁵=4-F-Ph;L²-R²=SO₂(4-t-butylphenyl)

To a solution of compound 54A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (50mg, 0.09 mmol) in DMF (1 mL) was added benzylamide (16 mL, 0.15 mmol),diisopropylethylamine (51 mL, 0.29 mmol) and HATU (45 mg, 0.19 mmol) andthe contents were stirred at ambient temperature for 18 h. Water (5 mL)was added and the organics were extracted with EtOAc (5 mL), washed withbrine and dried (MgSO₄). Purification by flash chromatography (CH₂Cl₂100% to 5% EtOAc in CH₂Cl₂) afforded 89 mg of the title compound as awhite solid. LC-MS (Method A): RT=4.33 min, (M+H)⁺ 599.

The following compounds were similarly prepared:

[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-morpholin-4-yl-methanone

LC-MS (Method A): RT=3.86 min, (M+H)⁺ 579.

[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-piperidin-1-yl-methanone

LC-MS (Method A): RT=4.33 min, (M+H)⁺ 577.

[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-pyrrolidin-1-yl-methanone

LC-MS (Method A): RT=4.14 min, (M+H)⁺ 563.

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylicacid ethylamide

LC-MS (Method A): RT=4.08 min, (M+H)⁺ 537.

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylicacid dimethylamide

LC-MS (Method A): RT=4.03 min, (M+H)⁺ 537.

Example 451-[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-ethanol(56A: R′=Me; R⁵=4-F-Phenyl; L²-R²=SO₂(4-t-butylphenyl)

A 3M solution of methylmagnesium bromide (294 μL, 0.88 mmol) was addedto a solution of compound 52A (R⁵=4-F-phenyl; L²-R²=SO₂(4-t-butylphenyl)(44 mg, 0.09 mmol) in THF (3 mL) and the contents were stirred atambient temperature for 4 h. A saturated solution of NH₄Cl was added andthe contents were partitioned between diethyl ether (10 mL) and water (5mL). The organics were extracted with EtOAc (5 mL), washed with brineand dried (MgSO₄). Purification by flash chromatography (CH₂Cl₂ 100% to5% EtOAc in CH₂Cl₂) afforded 10 mg of the title compound as a whitesolid. LC-MS (Method A): RT=4.25 min, (M+H)⁺ 510.

The following compounds were similarly prepared:

1-[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-propan-1-ol

LC-MS (Method A): RT=4.29 min, (M+H)⁺ 524.

[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-phenyl-methanol

LC-MS (Method A): RT=4.52 min, (M+H)⁺ 572.

Example 46[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-phenyl-methanone(57A: R¹=Ph; R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl)

Oxalyl chloride (15 μL, 0.17 mmol) in CH₂Cl₂ (1 mL) was cooled to −78°C. and DMSO (26 μL, 0.37 mmol) in CH₂Cl₂ (0.5 mL) was added. After 5min, compound 56A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (44 mg, 0.08mmol) was added and the contents were stirred for 20 min. Triethylamine(54 μL, 0.38 mmol) was added and the contents were warmed to ambienttemperature. The organics were partitioned between EtOAc (10 mL) andwater (10 mL) and washed with brine and dried (MgSO₄). Purification byflash chromatography (CH₂Cl₂ 100% to 15% EtOAc in CH₂Cl₂) afforded 18 mgof the title compound as colorless oil. LC-MS (Method A): RT=4.56 min,(M+H)⁺ 570.

Example 47(R)-1-Butyl-6-(toluene-4-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylicacid methyl ester (44A: R⁵=n-Butyl; L¹-R¹=CO₂Me;L²-R²=SO₂(4-Methylphenyl)

To compound 43A (L¹-R¹=CO₂Me; L²-R²=SO₂(4-methylphenyl)) (145 mg, 0.37mmol) in ethanol (1 mL) was added N-butyl hydrazinecarboxylic acidtert-butyl ester (70 mg, 0.37 mmol) (prepared as in J. Org. Chem. 2002,67, 8962-8969) in ethanol (4 mL) and the contents were stirred at 80° C.for 2 h. The solvents were then removed. The residue was dissolved indichloroethane (4 mL) and TFA (1 mL) was added and the contents werestirred at 60° C. for 1 h. Saturated aqueous NaHCO₃ (5 mL) was added andthe organics were extracted with CH₂Cl₂ (3×5 mL), washed with brine anddried (MgSO₄). Purification by flash chromatography (CH₂Cl₂ 100% to 30%EtOAc in CH₂Cl₂) afforded 135 mg of the title compound as a white solid.LC-MS (Method B): RT=16.71 min, (M+H)⁺ 444.

The following compound was similarly prepared:

(R)-6-(4-Methyl-benzenesulfonyl)-1-(cyclopentyl)-4a-(2-methoxy-ethoxymethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A) (M+H)⁺ 486.

Example 48(R)-6-(4-tert-Butyl-benzenesulfonyl)-4a-[1,3]dithian-2-ylidenemethyl-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene(58A: R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl)

2-Trimethylsilyl-1,3-dithiane (189 mL, 0.99 mmol) in THF (2 mL) wascooled to 0° C. and n-BuLi (0.62 mL, 0.99 mmol) was added. After 10 min,the temperature was lowered to −78° C. and a solution of compound 54A(R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (232 mg, 0.47 mmol) was added.After 30 min brine (5 mL) was added and the organics were extracted withCH₂Cl₂ (5 mL) and dried (MgSO₄). Purification by flash chromatography(CH₂Cl₂ 100% to 10% EtOAc in CH₂Cl₂) afforded 168 mg of the titlecompound as a white solid. LC-MS (Method A): RT=4.27 min, (M+H)⁺ 596.

Example 49[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-aceticacid methyl ester (59A: R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl)

To compound 58A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (165 mg, 0.28mmol) in methanol (12 mL) was added perchloric acid (86 μL, 1.42 mmol)and mercury^(II) chloride (301 mg, 1.11 mmol) and the contents wereheated at reflux for 2.5 h. The cooled solution was filtered and thefiltrate was concentrated. Purification by flash chromatography (CH₂Cl₂100% to 30% EtOAc in CH₂Cl₂) afforded 168 mg of the title compound as awhite solid. LC-MS (Method A): RT=4.38 min, (M+H)⁺ 538.

Example 502-[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-ethanol(60A: R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl)

To compound 59A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (128 mg, 0.24mmol) in CH₂Cl₂ (2.5 mL) was added DIBAL-H (950 μL, 1.0 M solution, 0.95mmol) at −78° C. and the contents were stirred for 1 h. The reaction wasquenched by the addition of water (5 mL). The organics were extractedwith CH₂Cl₂ (20 mL), washed with brine and dried (MgSO₄). Purificationby flash chromatography (CH₂Cl₂ 100% to 30% EtOAc in CH₂Cl₂) afforded104 mg of the title compound as a white solid. LC-MS (Method A): RT=3.90min, (M+H)⁺ 510.

Example 51(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-methoxy-ethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene(61A: R^(1A)=Me; R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl)

To compound 60A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (32 mg, 0.06mmol) in THF (1 mL) was added a sodium hydride (7.5 mg, 0.19 mmol) andiodomethane (12 μL, 0.19 mmol) and the contents were stirred at 75° C.for 18 h. The cooled contents were partitioned between EtOAc (10 mL) andwater (10 mL), washed with brine and dried (MgSO₄). Purification byflash chromatography (CH₂Cl₂ 100% to 15% EtOAc in CH₂Cl₂) afforded 12 mgof the title compound as colorless glass. LC-MS (Method A): RT=4.43 min,(M+H)⁺ 524.

Example 52[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-acetaldehyde(62A: R³=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl)

Oxalyl chloride (29 μL, 0.22 mmol) in CH₂Cl₂ (2 mL) was cooled to −78°C. and DMSO (38 μL, 0.48 mmol) in CH₂Cl₂ (1 mL) was added. After 5 min,compound 60A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (50 mg, 0.10 mmol)was added and the contents were stirred for 20 min. Triethylamine (51μL, 0.50 mmol) was added and the contents were warmed to ambienttemperature. The organics were partitioned between EtOAc (10 mL) andwater (10 mL), washed with brine and dried (MgSO₄). Purification byflash chromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 35 mgof the title compound as white solid. LC-MS (Method A): RT=3.87 min,(M+H)⁺ 508.

Example 53{2-[(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-4a-yl]-ethyl}-dimethylamine(63A: R^(1C)=R^(1D)=Me: R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl)

To a solution of compound 62A (R⁵=4-F-Ph; L²-R²=SO₂(4-t-butylphenyl) (35mg, 0.07 mmol) in dichloroethane (1 mL) was added dimethylamine (0.10mL, 0.21 mmol) and sodium triacetoxyborohydride (22 mg, 0.11 mmol). Thecontents were stirred for 18 h at ambient temperature, NaHCO₃ (2 mL) wasadded, and the organics were extracted with CH₂Cl₂ (10 mL), washed withbrine and dried (MgSO₄). Purification by flash chromatography(Amino-SPE: CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 61 mg of thetitle compound as an off white solid. LC-MS (Method A): RT=2.68 min,(M+H)⁺ 537.

The following compound was similarly prepared:

(R)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-(2-pyrrolidin-1-yl-ethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.93 min, (M+H)⁺ 563.

Example 54(4aS,8aS)-1-(4-Fluoro-phenyl)-4a-morpholin-4-ylmethyl-1,4,4a,5,7,8,8a,9-octahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-carboxylicacid tert-butyl ester (44B: L¹=CH₂; R¹=Morpholine; L²=CO₂-t-Butyl)

A mixture of compound 44A (L¹=CH₂; R¹=morpholine; L²=CO₂-t-butyl) (125mg, 0.27 mmol) and platinum oxide (9 mg, 0.04 mmol) in methanol (3 mL)was stirred for 2.5 h at ambient temperature under an atmosphere ofhydrogen. The solution was filtered and the filtrate was evaporated todryness. The residue was purified by preparative HPLC to yield the titlecompound as a white solid, 22 mg, LC-MS: RT=2.48 min, (M+H)⁺ 471,together with the cis-regioisomer, 35 mg, LC-MS (Method A): RT=2.61 min,(M+H)⁺ 471.

Example 55(4aS,8aS)-6-(4-tert-Butyl-benzenesulfonyl)-1-(4-fluoro-phenyl)-4a-morpholin-4-ylmethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-1,2,6-triazacyclopenta[b]naphthalene(44B: L¹=CH₂; R¹=Morpholine; L²-R²=SO₂(4-t-butylphenyl)

To compound 44B (L¹=CH₂; R′=morpholine; L²=CO₂-t-butyl) (22 mg, 0.05mmol) was added a 20% solution of TFA in CH₂Cl₂ (1 mL) and the contentswere stirred at ambient temperature for 1 h. The solvents were thenremoved. The residue was dissolved in CH₂Cl₂ (1 mL) and diisopropylethylamine (41 μL, 0.23 mmol) and 4-tert-butylphenylsulfonyl chloride (22 mg,0.09 mmol) were added and the contents were stirred for 18 h. Water (5mL) was added and the organics extracted with EtOAc (5 mL), washed withbrine and dried (MgSO₄). Purification by flash chromatography (CH₂Cl₂100% to 40% EtOAc in CH₂Cl₂) afforded 36 mg of the title compound as awhite solid. LC-MS (Method B): RT=9.84 min, (M+H)⁺ 567.

Example 564a-Benzyl-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2-diaza-6-azonia-cyclopenta[b]naphthalenehydrochloride (65A: R⁵=4-F-Phenyl; L¹-R¹=Benzyl)

Compound 64A (R⁵=4-F-phenyl; L¹-R¹=benzyl) (41 mg, 0.10 mmol) and ACE-Cl(20 μL, 0.18 mmol) were heated in dichloroethane (0.25 mL) at reflux for18 h. The contents were cooled and the solvent was removed. The residuewas dissolved in methanol (1 mL) and the contents were heated for 3 h atreflux. The solvent was removed to afford 21 mg of the title compound asa colorless glass which was used in subsequent examples without furtherpurification. LC-MS (Method A): RT=2.32 min, (M+H)⁺ 360.

The following compounds were similarly prepared:

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2-diaza-6-azonia-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.37 min. (M+H)⁺ 378.

Example 576-(4-tert-Butyl-benzenesulfonyl)-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1-2,6-triaza-cyclopenta[b]naphthalene(44A: R⁵=4-F-Phenyl; L¹=CH₂; R′=4-F-Phenyl; L²-R²=SO₂(4-t-butylphenyl)

Compound 65A (R⁵=4-F-phenyl; L¹-R¹=4-F-benzyl) (100 mg, 0.24 mmol) wasdissolved in CH₂Cl₂ (5 mL) and diisopropylethylamine (134 μL, 0.97 mmol)and 4-tert-butylphenylsulfonyl chloride (56 mg, 0.24 mmol) were addedand the contents were stirred for 18 h. Water (10 mL) was added and theorganics were extracted with EtOAc (15 mL), washed with brine and dried(MgSO₄). Purification by flash chromatography (CH₂Cl₂ 100% to 5% EtOAcin CH₂Cl₂) afforded 89 mg of the title compound as a cream solid. LC-MS(Method A): RT=4.82 min, (M+H)⁺ 574.

The following compounds were similarly prepared:

6-Benzenesulfonyl-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.31 min, (M+H)⁺ 518.

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(toluene-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.47 min, (M+H)⁺ 532.

6-(4-Fluoro-benzenesulfonyl)-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.34 min, (M+H)⁺ 536.

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-methanesulfonyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.78 min, (M+H)⁺ 456.

6-(Butane-1-sulfonyl)-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.26 min, (M+H)⁺ 498.

4a-Benzyl-1-(4-fluoro-phenyl)-6-(propane-2-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.01 min, (M+H)⁺ 466.

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(1-methyl-1H-imidazole-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.59 min, (M+H)⁺ 522.

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.38 min, (M+H)⁺ 589.

6-(6-tert-Butyl-pyridine-3-sulfonyl)-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.64 min, (M+H)⁺ 575.

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(4-morpholin-4-yl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=4.21 min, (M+H)⁺ 603.

Example 584a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-pyridin-4-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene(44A: R⁵=4-F-Phenyl; L¹-R¹=4-F-benzyl; L²-R²=4-Pyridinylmethyl)

To a solution of compound 65A (R⁵=4-F-Phenyl; =4-F-benzyl) (50 mg, 0.12mmol) in CH₂Cl₂ (1 mL) was added 4-pyridinecarboxaldehyde (12 μL, 0.12mmol) and sodium triacetoxyborohydride (39 mg, 0.18 mmol). The contentswere stirred for 18 h at ambient temperature, NaHCO₃ (2 mL) was added,and the organics were extracted with CH₂Cl₂ (10 mL) and washed withbrine and dried (MgSO₄). Purification by flash chromatography (CH₂Cl₂100% to 25% EtOAc in CH₂Cl₂) afforded 29 mg of the title compound as anoff-white solid. LC-MS (Method A): RT=2.71 min, (M+H)⁺ 469.

The following compounds were similarly prepared:

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-pyridin-3-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.54 min, (M+H)⁺ 469.

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-pyridin-2-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.55 min, (M+H)⁺ 469.

6-(6-tert-Butyl-pyridin-3-ylmethyl)-4a-(4-fluoro-benzyl)-1-(4-fluoro-phenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.07 min, (M+H)⁺ 525.

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-propyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.44 min, (M+H)⁺ 420.

4a-Benzyl-1-(4-fluoro-phenyl)-6-(1H-imidazol-4-ylmethyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.18 min, (M+H)⁺ 440.

4a-Benzyl-1-(4-fluoro-phenyl)-6-pyridin-4-ylmethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.65 min, (M+H)⁺ 451.

Example 594a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-phenyl-4,4a5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene(44A: R⁵=4-F-Phenyl; L¹-R¹=4-F-benzyl; L²-R²=Phenyl)

To a solution of compound 65A (R⁵=4-F-phenyl; L¹-R¹=4-F-benzyl) (70 mg,0.17 mmol) in CH₂Cl₂ (2.5 mL) was added copper^(II) acetate (61 mg, 0.34mmol) and phenyl boronic acid (41 mg, 0.34 mmol) and the contents werestirred at ambient temperature for 48 h. Water (2 mL) was added and theorganics were extracted with CH₂Cl₂ (10 mL) and washed with brine anddried (MgSO₄). Purification by flash chromatography (CH₂Cl₂ 100% to 25%EtOAc in CH₂Cl₂) afforded 15 mg of the title compound as an off-whitesolid. LC-MS (Method A): RT=4.84 min, (M+H)⁺ 454.

Example 604a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-carboxylicacid phenylamide (44A: R⁵=4-F-Phenyl; L¹-R¹=4-F-benzyl;L²-R²=CONHPhenyl)

Compound 65A (R⁵=4-F-phenyl; L¹-R¹=4-F-benzyl) (50 mg, 0.12 mmol) wasdissolved in CH₂Cl₂ (2 mL) and triethylamine (18 μL, 0.13 mmol) andphenyl isocyanate (14 μL, 0.13 mmol) were added and the contents stirredfor 18 h. Water (5 mL) was added and the organics were extracted withEtOAc (5 mL) and washed with brine and dried (MgSO₄). Purification byflash chromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂) afforded 10 mgof the title compound as a cream solid. LC-MS (Method A): RT=3.96 min,(M+H)⁺ 497.

Example 614a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-1,4,4a,5,7,8-hexahydrotriaza-cyclopenta[b]naphthalene-6-sulfonic acid phenylamide (44A:R⁵=4-F-Phenyl; L¹-R¹=4-F-Phenyl; L²-R²=SO₂NHPhenyl)

Compound 65A (R⁵=4-F-Phenyl; L¹-R¹=4-F-benzyl) (25 mg, 0.06 mmol) wasdissolved in CH₂Cl₂ (2 mL) and triethylamine (101 μL, 0.73 mmol) andphenyl sulfamoyl chloride (65 mg, 0.34 mmol) were added and the contentswere stirred for 18 h. Water (5 mL) was added and the organics wereextracted with EtOAc (5 mL) and washed with brine and dried (MgSO₄).Purification by flash chromatography (CH₂Cl₂ 100% to 5% EtOAc in CH₂Cl₂)afforded 15 mg of the title compound as a cream solid. LC-MS (Method A):RT=4.14 min, (M+H)⁺ 533.

The following compounds were similarly prepared:

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(morpholine-4-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=3.90 min, (M+H)⁺ 527.

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(4-methyl-piperazine-1-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene

LC-MS (Method A): RT=2.63 min, (M+H)⁺ 540.

4a-(4-Fluoro-benzyl)-1-(4-fluoro-phenyl)-6-(piperidine-1-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene:F

LC-MS (Method A): RT=4.36 min, (M+H)⁺ 525.

Example 622-[4a-Benzyl-1-(4-fluoro-phenyl)-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalen-6-yl]-N,N-dimethyl-acetamide(44A: (44A: R⁵=4-F-Phenyl; L¹-R¹=Benzyl; L²-R²=CH₂CONMe₂)

Compound 65A (R⁵=4-F-phenyl; L¹-R¹=benzyl) (42 mg, 0.11 mmol) wasdissolved in CH₂Cl₂ (2 mL) and sodium hydride (5 mg, 0.13 mmol) and2-chloro-N,N-dimethylacetamide (13 μL, 0.13 mmol) were added and thecontents were stirred for 18 h. Water (5 mL) was added and the organicswere extracted with EtOAc (5 mL) and washed with brine and dried(MgSO₄). Purification by flash chromatography (CH₂Cl₂ 100% to 10% EtOAcin CH₂Cl₂) afforded 9 mg of the title compound as a yellow oil LC-MS(Method A): RT=2.34 min, (M+H)⁺ 445.

Example 63 Glucocorticoid Receptor Binding Assay

The following is a description of an assay for determining theinhibition of dexamethasone binding of the Human RecombinantGlucocorticoid Receptor:

Binding protocol: Compounds were tested in a binding displacement assayusing human recombinant glucocorticoid receptor with ³H-dexamethasone asthe ligand. The source of the receptor was recombinantbaculovirus-infected insect cells. This GR was a full-length steroidhormone receptor likely to be associated with heat-shock and otherendogenous proteins.

The assay was carried out in v-bottomed 96-well polypropylene plates ina final volume of 200 μl containing 0.5 nM GR solution, 2.5 nM3H-dexamethasone (Amersham TRK 645) in presence of test compounds, testcompound vehicle (for total binding) or excess dexamethasone (20 μM, todetermine non-specific binding) in an appropriate volume of assaybuffer.

For the Primary Screen, test compounds were tested at 1 μM in duplicate.These compounds were diluted from 10 mM stock in 100% DMSO. Afterdilution to 100 μM, 5 μl were added to 245 μl assay buffer to obtained 2μM compound and 2% DMSO.

For the IC₅₀ determinations, test compounds were tested at 6concentrations in duplicate (concentration range depends on % inhibitionbinding that was obtained in the Primary Screen,). Test compounds werediluted from 10 mM stock in 100% DMSO. The tested solutions wereprepared at 2× final assay concentration in 2% DMSO/assay buffer.

All reagents and the assay plate were kept on ice during the addition ofreagents. The reagents were added to wells of a v-bottomed polypropyleneplate in the following order: 50 μl of 10 nM 3H-dexamethasone solution,100 μl of TB/NSB/compound solution and 50 μl of 2 nM GR solution. Afterthe additions, the incubation mixture was mixed and incubated for 2.5hrs at 4° C.

After 2.5 hrs incubation, unbound counts were removed with dextrancoated charcoal (DCC) as follows: 25 μl of DCC solution (10% DCC inassay buffer) was added to all wells and mixed (total volume 225 μl).The plate was centrifuged at 4000 rpm for 10 minutes at 4° C. 75 μl ofthe supernatants (i.e. ⅓ of total volume) was carefully pipetted into anoptiplate. 200 μl of scintillation cocktail were added (Microscint-40,Packard Bioscience. B.V.). The plate was vigorously shaken for approx.10 minutes and counted on Topcount.

For the IC₅₀ determinations, the results were calculated as % inhibition[³H]-dexamethasone bound and fitted to sigmoidal curves (fixed to 100and 0) to obtain IC₅₀ values (concentration of compound that displaces50% of the bound counts). The IC₅₀ values were converted to K_(i) (theinhibition constant) using the Cheng-Prusoff equation. Test results arepresented in Table I for selected compounds of the Invention. Compoundswith a K_(i) value of <10 nM are designated with ***; compounds with aK_(i) value of 10-100 nM are designated with **; compounds with a K_(i)of >100 nM are designated with *. A—indicates that the compound was nottested.

Reagents: Assay buffer: 10 mM potassium phosphate buffer pH 7.6containing 5 mM DTT, 10 mM sodium molybdate, 100 μM EDTA and 0.1% BSA.

TABLE I GR Binding GR Functional

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Example 64 Selectivity Binding assays

Selectivity binding assays were performed against human estrogen (ERα),progesterone (PR), androgen (AR) and mineralocorticoid (MR) receptors.The selectivity assays were carried out in the same assay buffer andvolumes as the GR binding assay and DCC was used to separate free frombound label.

Mineralocorticoid binding assay: MR was obtained from Sf9 cells infectedwith recombinant baculovirus containing MR, and the MR was isolatedaccording to the method of Binart et al (Binart, N.; Lombes, M.;Rafestin-Oblin, M. E.; Baulieu, E. E. Characterisation of humanmineralocorticoid receptor expressed in the baculovirus system. PNAS US,1991, 88, 10681-10685). Compounds were tested against an appropriatedilution of the MR (determined for each batch of receptor) with 2.4 nMof [³H] aldosterone (Perkin Elmer NET419) and incubated for 60 mins atroom temperature.

Estrogen binding assay: Compounds were tested for displacement of 0.56nM [³H]-estradiol (Perkin Elmer NET517) binding to 0.5 nM ERα (obtainedfrom PanVera 26467A) following an incubation period of 90 mins at roomtemperature.

Progesterone binding assay: Compounds were tested for displacement of 3nM [³H]-progesterone (Perkin Elmer NET381) binding to 1 nM PR (obtainedfrom PanVera 24900). This assay was incubated for 120 mins at 4° C.

Androgen binding assay: Compounds were tested, in triplicate, fordisplacement of 6 nM [³H]-dihydrotestosterone (Perkin Elmer NET453)binding to 3 nM PR (obtained from PanVera 24938). This assay wasincubated overnight at 4° C.

Compounds in Table I inhibited <50% binding at the MR, ER, PR, and ARreceptors under the above protocols when tested at 10 μM.

Example 65 GR Functional Assay Using SW1353/MMTV-5 Cells

SW1353/MMTV-5 is an adherent human chondrosarcoma cell line thatcontains endogenous glucocorticoid receptors. It was transfected with aplasmid (pMAMneo-Luc) encoding firefly luciferase located behind aglucocorticoid-responsive element (GRE) derived from a viral promoter(long terminal repeat of mouse mammary tumor virus). A stable cell lineSW1353/MMTV-5 was selected with geneticin, which was required tomaintain this plasmid. This cell line was thus sensitive toglucocorticoids (dexamethasone) leading to expression of luciferase(EC₅₀ ^(dex) 10 nM). This dexamethasone-induced response was graduallylost over time, and a new culture from an earlier passage was started(from a cryo-stored aliquot) every three months.

In order to test for a GR-antagonist, SW1353/MMTV-5 cells were incubatedwith several dilutions of the compounds in the presence of 5xEC₅₀ ^(dex)(50 nM), and the inhibition of induced luciferase expression wasmeasured using a luminescence in a Topcounter (LucLite kit from PerkinElmer). For each assay, a dose-response curve for dexamethasone wasprepared in order to determine the EC₅₀ ^(dex) required for calculatingthe K_(i) from the IC₅₀'s of each tested compound. Test results arepresented in Table I for selected compounds of the Invention. Compoundswith a K_(i) value of <10 nM are designated with ***; compounds with aK_(i) value of 10-100 nM are designated with **; compounds with a K_(i)of >100 nM are designated with *. A—indicates that the compound was nottested.

SW1353/MMTV-5 cells were distributed in 96-well plates and incubated inmedium (without geneticin) for 24 hrs (in the absence of CO₂). Dilutionsof the compounds in medium+50 nM dexamethasone were added and the platesfurther incubated for another 24 hrs after which the luciferaseexpression is measured.

Example 66 Cytotoxicity Assay Using SW1353/Luc-4 Cells

In order to exclude the possibility that compounds inhibit thedexamethasone-induced luciferase response (GR-antagonist) due to theircytotoxicity or due to their direct inhibition of luciferase, a SW1353cell line was developed that constitutively expressed fireflyluciferase, by transfection with plasmid pcDNA3.1-Luc and selection withgeneticin. The cell line SW1353/Luc-4 was isolated that constitutivelyexpressed luciferase.

SW1353/Luc-4 cells were distributed in 96-well plates and incubated (noCO₂) for 24 hrs, after which compound dilutions (without dexamethasone)were added. After a further 24 hrs incubation, luciferase expression wasmeasured using the “LucLite” assay. The compounds listed in Table I didnot demonstrate cytotoxicity in this assay when tested at aconcentration of 1-3 micromolar.

Example 67 MR and PR Functional Assays Using T47D/MMTV-5 Cells

T47D/MMTV-5 is an adherent human breast carcinoma cell line containingendogenous mineralocorticoid- (MR) and progesterone (PR) receptors. Asfor the SW1353 cell line, T47D cells was transfected with the samepMAMneo-Luc plasmid, and stable lines selected with geneticin. A cellline T47D/MMTV-5 was isolated which responded to aldosterone (EC₅₀^(ald) 100 nM), and progesterone (EC₅₀ ^(prog) 10 nM), leading toexpression of luciferase.

As for the GR assay to test for MR- or PR-antagonists, the T47D/MMTV-5cells were incubated with several dilutions of the compounds in thepresence of the 5xEC₅₀ of the agonist aldosterol (EC₅₀ ^(ald) 100 nM) orprogesterone (EC₅₀ ^(prog) 10 nM), respectively. For each assay, a doseresponse curve was prepared for both aldosterone and progesterone.

T47D/MMTV-5 cells were distributed in 96-well plates (100P in RPMI1640medium+10% Charcoal stripped FCS. The cells were incubated for 24 hrs inthe CO₂-oven. A volume of 100 μl of the compound dilutions inmedium+agonist (500 nM aldost; 50 nM progest) were added, and the platesfurther incubated for another 24 hrs after which the luciferaseexpression was measured.

Compounds of the Invention did not display MR or PR functional activityin these assays. For example, the compound of Example 29 inhibited only8% of the PR agonist response and 10% of the MR functional response whentested at a concentration of 3 micromolar.

1. A compound having the formula:

wherein, L¹ and L² are members independently selected from a bond, —O—,—S—, S(O)—, —S(O₂)—, —C(O)—, —C(O)O—, —C(O)NH—, substituted orunsubstituted alkylene, and substituted or unsubstituted heteroalkylene;the dashed line b is optionally a bond; the ring A is a member selectedfrom substituted or unsubstituted 5 to 6 membered heterocycloalkyl, andsubstituted or unsubstituted heteroaryl; R¹ is a member selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR^(1A),—NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), —C(O)OR^(1A), wherein R^(1A) is amember selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl;R^(1C) and R^(1D) are members independently selected from substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein R^(1C) and R^(1D) are optionallyjoined to form a substituted or unsubstituted ring with the nitrogen towhich they are attached, wherein said ring optionally comprises anadditional ring nitrogen, and R² is a member selected from substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —S(O₂)R^(2A), —S(O₂)NR^(2B)R^(2C), and═NOR^(2D), wherein R^(2A), R^(2B), R^(2C), and R^(2D) are membersindependently selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. 2.The compound of claim 1, wherein A is a member selected from:unsubstituted 5 to 6 membered heterocycloalkyl comprising at least oneheteroatom selected from N, O and S; substituted 5 to 6 memberedheterocycloalkyl comprising 1 to 3 substituents and at least one ringheteroatom selected from N, O and S; unsubstituted aryl comprising atleast one heteroatom selected from N, O and S; and substituted arylcomprising 1 to 3 substituents and at least one ring heteroatom selectedfrom N, O and S.
 3. The compound of claim 1, wherein A is a memberselected from substituted or unsubstituted pyrrolidinyl, substituted orunsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl,substituted or unsubstituted imidazolyl, substituted or unsubstitutedfuranyl, substituted or unsubstituted oxazolyl, substituted orunsubstituted isoxazolyl, substituted or unsubstituted thienyl,substituted or unsubstituted thiazolyl, substituted or unsubstitutedisothiazolyl, substituted or unsubstituted pyridinyl, substituted orunsubstituted pyrimidinyl, and substituted or unsubstituted pyrazinyl.4. The compound of claim 1, wherein A is a substituted or unsubstitutedpyrazolyl.
 5. The compound of claim 1, wherein A is substituted with amember selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaryl, —NR^(3A)R^(3B), and —OR^(3C), wherein R^(3A) and R^(3B) aremembers independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heterocycloalkyl, and substituted orunsubstituted heteroaryl, wherein R^(3A) and R^(3B) are optionallyjoined to form a substituted or unsubstituted ring with the nitrogen towhich they are attached, wherein said ring optionally comprises anadditional ring heteroatom, and R^(3C) is a member selected fromsubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.
 6. The compound of claim 5,wherein A is substituted with a member selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,and substituted or unsubstituted heteroaryl.
 7. The compound of claim 1having the formula

wherein, the dashed ring represents unsaturated, partially saturated, orfully saturated bonds within ring E; Z¹ is a member selected from —NR⁵—,═N—, —O—, and —S—, wherein R⁵ is a member selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl,and substituted or unsubstituted aryl; Z² is a member selected from—CR^(6A)R^(6B)—, ═CR^(6A)—, —C(O)—, —NR^(6C)—, ═N—, —O—,—CR^(6A)R^(6B)—NR^(6C)—, ═CR^(6A)—NR^(6C)—, —CR^(6A)R^(6B)—N═, and═CR^(6A)—N═, wherein R^(6C) is a member selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, R^(6A) and R^(6B) are membersindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted aryl, —NR^(6A1)R^(6A2), and —OR^(6A3), wherein R^(6A1) andR^(6A2) are members independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein  R^(6A1) and R^(6A2) are optionallyjoined to form a substituted or unsubstituted ring with the nitrogen towhich they are attached, wherein said ring optionally comprises anadditional ring heteroatom, and R^(6A3) is a member selected fromsubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, wherein R^(6A) and R^(6C) areoptionally joined together to form a substituted or unsubstituted ring,wherein said ring optionally comprises an additional ring heteroatom; Z³is a member selected from —CR^(7A)R^(7B)—, ═CR^(7A)—, —C(O)—, —NR^(7C)—,═N—, —O—, and —S—, wherein R^(7C) is a member selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroaryl, and substituted or unsubstituted aryl, R^(7A) and R^(7B) areindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted aryl, —NR^(7A1)R^(7A2), and —OR^(7A3), wherein R^(7A1) andR^(7A2) are members independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein R^(7A1) and R^(7A2) are optionallyjoined to form a substituted or unsubstituted ring with the nitrogen towhich they are attached, wherein said ring optionally comprises anadditional ring heteroatom, and R^(7A3) is a member selected fromsubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; wherein R⁵ is optionally joinedwith R^(6A) or R^(6C) to form a substituted or unsubstituted ring,wherein said ring optionally comprises an additional ring heteroatom;wherein R^(7A) is optionally joined with R^(6A) or R^(6C) to form asubstituted or unsubstituted ring, wherein said ring optionallycomprises an additional ring heteroatom; and wherein R^(7C) isoptionally joined with R^(6A) or R^(6C) to form a substituted orunsubstituted ring, wherein said ring optionally comprises an additionalring heteroatom.
 8. The compound of claim 7, wherein Z¹ is —NR⁵—; Z² is═N—; and Z³ is ═CR^(7A)—.
 9. The compound of claim 8, wherein R^(7A) ishydrogen; and R⁵ is a member selected from hydrogensubstituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted arylalkyl and substituted or unsubstitutedheteroarylalkyl.
 10. The compound of claim 7, wherein R⁵ has theformula:

wherein, R^(5A) is a member selected from hydrogen, halogen, —OR^(5A1),—NR^(5A2)R^(5A3), —S(O₂)NR^(5A2)R^(5A3), —CN, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, wherein R^(5A1) is a member selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl, andR^(5A2) and R^(5A3) are members independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; m is an integer from 0 to 10;and n is an integer from 1 to
 5. 11. The compound of claim 10, wherein nis 1; m is 0 or 1; and R^(5A1), R^(5A2) and R^(5A3) are hydrogen. 12.The compound of claim 7, wherein Z¹ is —NR⁵—; Z² is ═CR^(6A)—; and Z³ is═N—.
 13. The compound of claim 12, wherein R⁵ is a member selected fromhydrogen and substituted or unsubstituted aryl.
 14. The compound ofclaim 8, wherein R⁵ and R^(7A) are hydrogen and b is a bond.
 15. Thecompound of claim 1, wherein R¹ is a member selected from substituted orunsubstituted (C₁-C₁₀) alkyl, substituted or unsubstituted 2-10 memberedheteroalkyl, substituted or unsubstituted (C₃-C₇) cycloalkyl,substituted or unsubstituted 3-7 membered heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. 16.The compound of claim 1, wherein R¹ has the formula:

wherein, q is an integer selected from 1 to 5; R^(1B) is a memberselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl,—NR^(1B1)R^(1B2), —OR^(1B3), and —C(O)NR^(1B4)R^(1B5) wherein R^(1B1)and R^(1B2) are members independently selected from hydrogen,substituted alkyl, substituted or unsubstituted heteroalkyl, substitutedor unsubstituted heterocycloalkyl, and substituted or unsubstitutedheteroaryl, wherein R^(1B1) and R^(1B2) are optionally joined to form asubstituted or unsubstituted ring with the nitrogen to which they areattached, wherein said ring optionally comprises an additional ringheteroatom, and R^(1B3) is a member selected from hydrogen, substitutedor unsubstituted heteroalkyl comprising a nitrogen, substituted orunsubstituted heterocycloalkyl comprising a ring nitrogen, substitutedor unsubstituted heteroaryl comprising a ring nitrogen, and alkylsubstituted with a substituted or unsubstituted heteroalkyl comprising anitrogen, substituted or unsubstituted heterocycloalkyl comprising aring nitrogen, and substituted or unsubstituted heteroaryl comprising aring nitrogen; and R^(1B4) and R^(1B5) are members independentlyselected from hydrogen, substituted or unsubstituted heteroalkylcomprising a nitrogen, substituted or unsubstituted heterocycloalkylcomprising a ring nitrogen, substituted or unsubstituted heteroarylcomprising a ring nitrogen, and alkyl substituted with a substituted orunsubstituted heteroalkyl comprising a nitrogen, substituted orunsubstituted heterocycloalkyl comprising a ring nitrogen, andsubstituted or unsubstituted heteroaryl comprising a ring nitrogen,wherein R^(1B4) and R^(1B5) are optionally joined to form a substitutedor unsubstituted ring with the nitrogen to which they are attached,wherein said ring optionally comprises a heteroatom.
 17. The compound ofclaim 16, wherein q is an integer selected from 1 to 3; R^(1B) is amember selected from hydrogen, substituted alkyl, substituted orunsubstituted heteroalkyl, substituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted aryl, and substituted orunsubstituted heteroaryl.
 18. The compound of claim 16, wherein R¹ hasthe formula:

wherein, R^(1B) is a member selected from hydrogen, —NR^(1B1)R^(1B2),—OR^(1B3), substituted or unsubstituted (C₁-C₁₀) alkyl, substituted orunsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted(C₃-C₇)cycloalkyl, substituted or unsubstituted 3-7 memberedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.
 19. The compound of claim 16, wherein R^(1B)is a member selected from —C(O)NR^(1B4)R^(1B5) and substituted orunsubstituted heteroaryl comprising a ring nitrogen, wherein R^(1B4) andR^(1B5) are members independently selected from hydrogen, substituted orunsubstituted heteroalkyl comprising a nitrogen, substituted orunsubstituted heterocycloalkyl comprising a ring nitrogen, substitutedor unsubstituted heteroaryl comprising a ring nitrogen, and alkylsubstituted with a substituted or unsubstituted heteroalkyl comprising anitrogen, substituted or unsubstituted heterocycloalkyl comprising aring nitrogen, and substituted or unsubstituted heteroaryl comprising aring nitrogen, wherein R^(1B4) and R^(1B5) are optionally joined to forma substituted or unsubstituted ring with the nitrogen to which they areattached, wherein said ring optionally comprises a heteroatom.
 20. Thecompound of claim 19, wherein R^(1B1), R^(1B2), R^(1B3), R^(1B4) andR^(1B5) are members independently selected from hydrogen and asubstituted or unsubstituted ring, wherein said ring optionallycomprises a nitrogen atom and at least one additional ring heteroatom.21. The compound of claim 1, wherein R² is a member selected fromsubstituted or unsubstituted (C₁-C₁₀) alkyl, substituted orunsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted(C₃-C₇) cycloalkyl, substituted or unsubstituted 3-7 memberedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.
 22. The compound of claim 1, R^(2A), R^(2B),R^(2C), and R^(2D) are members independently selected from substitutedor unsubstituted (C₁-C₁₀) alkyl, substituted or unsubstituted 2-10membered heteroalkyl, substituted or unsubstituted (C₃-C₇) cycloalkyl,substituted or unsubstituted 3-7 membered heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. 23.The compound of claim 1, R² has the formula:

wherein, R^(2G) is a member selected from hydrogen, halogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl; J is a substituted or unsubstituted ringselected from substituted or unsubstituted (C₃-C₇) cycloalkyl,substituted or unsubstituted 3-7 membered heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl; t isan integer from 0 to 5; and X is a member selected from a bond, —S(O₂)—,and —S(O₂)N^(2I)—, wherein R^(2I) is a member selected from hydrogen,substituted or unsubstituted alkyl, and substituted or unsubstitutedheteroalkyl.
 24. The compound of claim 23, wherein R^(2G) is a memberselected from hydrogen, substituted or unsubstituted (C₁-C₁₀) alkyl,substituted or unsubstituted 2-10 membered heteroalkyl, substituted orunsubstituted (C₃-C₇)cycloalkyl, substituted or unsubstituted 3-7membered heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; J is a substituted orunsubstituted ring selected from substituted or unsubstituted 3-7membered heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; t is 1; and R^(2I) is hydrogen.25. The compound of claim 23, wherein R^(2G) is a branched or unbranched(C₁-C₁₀)alkyl.
 26. The compound of claim 23, wherein X is —S(O₂)—. 27.The compound of claim 1, wherein L¹ and L² are members independentlyselected from a bond and unsubstituted (C₁-C₆) alkylene.
 28. Thecompound of claim 1, wherein the dashed line b is a bond; R¹ issubstituted or unsubstituted benzyl; and R² has the formula:

wherein, R^(2G) is a member selected from hydrogen, halogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl, J is a substituted or unsubstituted ringselected from substituted or unsubstituted (C₃-C₇) cycloalkyl,substituted or unsubstituted 3-7 membered heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl, t isan integer fro 0 to 5, and X is —S(O₂)—; L¹ is a bond; and L² is a bond.29. A method of treating a disorder or condition through modulating aglucocorticoid receptor, the method comprising administering to asubject in need of such treatment, an effective amount of the compoundof one of claims 1-28.
 30. A method of treating a disorder or conditionthrough antagonizing a glucocorticoid receptor, the method comprisingadministering to a subject in need of such treatment, an effectiveamount of the compound of one of claims 1-28.
 31. A method of modulatinga glucocorticoid receptor including the steps of contacting aglucocorticoid receptor with an effective amount of the compound of oneof claims 1-28 and detecting a change in the activity of theglucocorticoid receptor.
 32. A pharmaceutical composition comprising apharmaceutically acceptable excipient and the compound of one of claims1-28.